Process of making alpha-aminooxyketone/alpha-aminooxyaldehyde and alpha-hydroxyketone/alpha-hydroxyaldehyde compounds and a process making reaction products from cyclic alpha, beta-unsaturated ketone substrates and nitroso substrates

ABSTRACT

The present invention is directed to a process of making α-aminooxyketone and α-hydroxyketone compounds. The synthetic pathway generally involves reacting an aldehyde or ketone substrate and a nitroso substrate in the presence of a catalyst of the formula (IV): 
     
       
         
         
             
             
         
       
     
     wherein X a -X c  represent independently nitrogen, carbon, oxygen or sulfur and Z represents a 4 to 10-membered ring with or without a substituent and optionally a further step to convert the α-aminooxyketone compound formed to the α-hydroxyketone compound. The present invention results in α-aminooxyketone and α-hydroxyketone compounds with high enantioselectivity and high purity. The present invention is also directed to a catalytic asymmetric O-nitroso Aldol/Michael reaction. The substrates of this reaction are generally cyclic α,β-unsaturated ketone substrate and a nitroso substrate. This methodology generally involves reacting the cyclic α,β-unsaturated ketone substrate and the nitroso substrate in the presence of a proline-based catalyst, to provide a heterocyclic product.

INCORPORATION BY REFERENCE

This application is a divisional of U.S. application Ser. No. 12/578,836filed Oct. 14, 2009, now pending, which is a divisional of U.S.application Ser. No. 11/506,590 filed Aug. 18, 2008, now U.S. Pat. No.7,872,123 B2 issued on Jan. 18, 2011, which is a continuation in part(CIP) of PCT/US2005/005426 filed Feb. 18, 2005, which claims the benefitof U.S. Provisional Application Ser. No. 60/564,048 filed Apr. 20, 2004and Japanese Patent Application No. 2004-44540 filed Feb. 20, 2004, theentire contents of which are incorporated herein by reference.

STATEMENT OF FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The subject matter of this application was in part funded by theNational Institutes of Health (GM068433-01). The government may havecertain rights in this invention.

The foregoing applications, and all documents cited therein or duringtheir prosecution (“appln cited documents”) and all documents cited orreferenced in the application cited documents, and all documents citedor referenced herein (“herein cited documents”), and all documents citedor referenced in herein cited documents, together with anymanufacturer's instructions, descriptions, product specifications, andproduct sheets for any products mentioned herein or in any documentincorporated by reference herein, are hereby incorporated herein byreference, and may be employed in the practice of the invention.

FIELD OF THE INVENTION

This invention relates to a process of making α-aminoxyketones orα-hydroxyketones with high enantioselectivity and high purity and alsodescribes the catalytic methods involved in the process of makingα-aminoxyketones or α-hydroxyketones through a highly enantioselectiveO-nitroso aldol reaction between an aldehyde or ketone and a nitrosocompound. The invention is also directed to a catalytic asymmetricO-nitroso Aldol/Michael reaction between a cyclic α,β-unsaturated ketonesubstrate and a nitroso compound. In both the enantioselective O-nitrosoaldol and nitrso Aldol/Michael reactions, the chiral catalyst employedis derived from proline.

BACKGROUND OF THE INVENTION

α-Hydroxyketone compounds are found in natural products and frequentlyin the molecule framework of pharmaceutical compounds. They aresynthetic equivalents for aldose compounds, e.g. pentoses and hexoses,and are very important synthetic building blocks which can lead tovarious physiologically active materials, medicines and intermediates inthe synthesis of liquid crystalline materials.

α-Hydroxyketones can be obtained readily with high purity by asymmetricoxidation of carbonyl compounds. However, asymmetric oxidation of theα-position of the carbonyl group by the usual methods requires atwo-step process. First, the preparation and isolation of an enolate,and second, the use of a relatively expensive oxygen-introducingreagent, which have the problem of low atom efficiency.

Other methods for direct preparation of chiral α-hydroxyketones withoutisolation of an enolate have been reported. These methods generallyinvolve synthesizing enantioenriched α-aminooxyketones, which areprecursors to α-hydroxyketones.

Previously disclosed were methods which used the amino acid proline as acatalyst and nitrosobenzene as an oxygen-introducing reagent to prepareα-aminooxyketones (see e.g. Brown, S. P., Brochu, M. P., Sinz, C. J. &MacMillan, D. W. C. (2003) J. Am. Chem. Soc. 125, 10808-10809; Zhong, G.(2003) Angew. Chem. Int. Ed 42, 4247-4250; Hayashi, Y., Yamaguchi, J.,Hibino, K. & Shoji, M. (2003) Tetrahedron Lett. 44, 8293-8296). However,many problems remain unsolved with this method, including a lack ofcatalytic efficiency (10 to 20 mol % catalyst is needed) and aninability to consistently reproduce results. Moreover, it is known thata second unwanted oxygen atom may be introduced via a side reaction witha second equivalent of nitrosobenzene.

Alternatively, it was reported that α-aminooxyketone could be obtainedin high yield from an alkylsilyl ether and nitrosobenzene withalkylsilyl triflate as a Lewis Acid catalyst (see e.g. Momiyama, N.,Yamamoto, H. (2002) Angew. Chem. Int. Ed 41, 2986-2987) and also from analkyltin enolate and nitrosobenzene with Ag-BINAP as a catalyst (seee.g. Momiyama, N., Yamamoto, H. (2003) J. Am. Chem. Soc. 125,6038-6039).

Additionally, other methods have been disclosed to produce aldolproducts from the condensation reaction of carbonyl compounds by: (1)using a substrate with an ether or alcohol unit in the molecule withliquid CO₂, or supercritical CO₂ as a solvent (see e.g. Japanese Patent2002-No. 284729); (2) running the reaction in water using boronic acidor a phase transfer catalyst or Brönsted acid (see e.g. Japanese Patent2002-No. 275120); or (3) using a lanthanide triflate with a chiral crownether (see e.g. Japanese Patent 2002-No. 200428).

Despite these methods for synthesizing α-aminooxyketone orα-hydroxyketone compounds, there is still a need in the art for aprocess which can produce α-aminooxyketone or α-hydroxyketone compoundswith sufficient enantioselectivity, purity and/or reproducibility ofresults to enable these compounds to be suitable for use as syntheticbuilding blocks or intermediates in a synthetic process.

One of the most intensely studied areas in chemical synthesis at presentis the development of new enantioselective processes which are catalyzedby simple organic molecules. By using a proline-based chiral catalyst,we have discovered a reaction process which provides a method for thecatalytic asymmetric synthesis of α-aminooxyketones via an O-nitrosoAldol reaction between an aldehyde or ketone and a nitroso compound.These compounds are easily converted into the synthetically importantenatioenriched α-hydroxyketones.

Furthermore, we have developed a process for producing bicyclo ketoneswhich contain nitrogen and oxygen heteroatoms via an asymmetricO-nitroso Aldol/Michael reaction between an α,β-unsaturated cyclicketone with a nitroso compound. The product generated from this reactionis a Diels-Alder adduct that usually is formed through a typicalDiels-Alder reaction. However, in the tandem O-Nitroso Aldol/Michaelreactions described herein, the regiochemistry of the Diels-Alder adductis opposite that of the normal nitroso Diels-Alder reaction. Owing tothe ability to control both regiochemistry and stereochemistry, thesecatalytic asymeetric Aldol/Michael reactions provide novel routes toimportant or previously unaccessible heterocyclic compounds.

Citation or identification of any document in this application is not anadmission that such document is available as prior art to the presentinvention.

SUMMARY OF THE INVENTION

The invention is based, in part, on applicants' development of a processof making α-aminoxyketones or α-hydroxyketones with highenantioselectivity and high purity and a method of preparing bicycloketones which contain nitrogen and oxygen heteroatoms through reactingan α,β-unsaturated cyclic ketone with a nitroso compound, where theregiochemistry of this product is opposite that of the normal nitrosoDiels-Alder reaction.

The object of the invention provides a method to prepareα-aminooxyketone (which are precursors of α-hydroxyketones) and todevelop new synthetic routes for making saccharide related compounds orglycosylation of compounds, especially those compounds with anti-canceror anti-HIV effects.

Another object of the invention is to provide a method of preparingbicyclo ketones which contain nitrogen and oxygen heteroatoms whenreacting an α,β-unsaturated cyclic ketone with a nitroso compound, wherethe regiochemistry of this product is opposite that of the normalnitroso Diels-Alder reaction.

It is noted that in this disclosure and particularly in the claimsand/or paragraphs, terms such as “comprises”, “comprised”, “comprising”and the like can have the meaning attributed to it in U.S. Patent law;e.g., they can mean “includes”, “included”, “including”, and the like;and that terms such as “consisting essentially of” and “consistsessentially of” have the meaning ascribed to them in U.S. Patent law,e.g., they allow for elements not explicitly recited, but excludeelements that are found in the prior art or that affect a basic or novelcharacteristic of the invention.

These and other embodiments are disclosed or are apparent from andencompassed by, the following Detailed Description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Structure of intermediates in the reaction pathway of apyrrolidine enamine and nitrosobenzene.

FIG. 2 Proposed transition states for enantioselective reactions betweenketones (left) or aldehydes (right) with nitrosobenzene.

FIG. 3. General reaction schemes for Examples 5a-12a.

FIG. 4. Comparison of effects of different catalysts of formula (IV).

FIG. 5. Effect of mixed catalysts on product formation.

FIGS. 6A and 6B. Process to determine absolute configuration ofα-aminooxy compounds.

DETAILED DESCRIPTION

This invention provides a method to prepare α-aminooxyketone (which areprecursors of α-hydroxyketones) which comprises reacting an aldehyde offormula (I) or ketone of formula (II):

with a nitroso compound of formula (IIIa) or (IIIb):

in the presence of a solvent and a catalyst of formula (IV):

wherein:

-   -   R, R¹ and R² independently represent either hydrogen; a        substituted or unsubstituted alkyl group; a substituted or        unsubstituted alkoxy group; a substituted or unsubstituted        alkoxycarbonyl group; a substituted or unsubstituted aryl group;        or    -   R¹ and R² together form a cycloalkyl ring;    -   R³ is each independently selected from the group consisting of        hydrogen, halogen, —OR⁵, —OC(O)R⁵, —CN, —C(O)R⁵, —CO₂R⁵,        —C(O)NR⁵R^(5′), —NO₂, —NR⁵R^(5′), —NRC(O)R⁵, —NR⁵CO₂R^(5′),        —NR⁵S(O)₂R^(5′), —SR⁵, —S(O)R⁵, —S(O)₂R⁵, —S(O)₂NR⁵R^(5′), C₁₋₈        alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl,        5- to 10-membered heteroaryl, and 3- to 10-membered        heterocyclyl; wherein        -   each R⁵ and R^(5′) may be independently selected from the            group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈            alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;    -   n is an integer from 0-5;    -   R⁴ is substituted or unsubstituted alkyl;    -   X^(a), X^(b) and X^(c) independently represent oxygen; sulfur;        substituted or unsubstituted nitrogen; or substituted or        unsubstituted carbon with the bonds between X^(a)—X^(b),        X^(b)—X^(c) and X^(a)—C (adjacent to nitrogen on pyrrolidine        ring) being single or optionally double bonds;    -   Z represents a substituted or unsubstituted 4 to 10-membered        ring (herein referred to as “the Z ring”) which optionally        contains up to three additional heteroatoms; and    -   the bond between the two rings is in the (L) or optionally (D)        configuration.        Another embodiment of the invention is where:    -   R, R¹ and R² independently represent either hydrogen; a        substituted or unsubstituted        -   C₁-C₈ alkyl group; a substituted or unsubstituted C₁-C₈            alkoxy group; a substituted or unsubstituted C₁-C₈            alkoxycarbonyl group; a substituted or unsubstituted aryl            group, wherein the groups when substituted are substituted            by the group consisting of hydrogen, halogen, —OR⁴,            —OC(O)R⁴, —CN, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁴R⁵, —NO₂, —NR⁴R⁵,            —NRC(O)R⁴, —NR⁴CO₂R⁵, —NR⁴S(O)₂R⁵, —SR⁴, —S(O)R⁴, —S(O)₂R⁴,            —S(O)₂NR⁴R⁵, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to            10-membered heteroaryl, and 3- to 10-membered heterocyclyl;            or    -   R¹ and R² together form a C₃-C₈ cycloalkyl ring;    -   R³ is each independently selected from the group consisting of:        -   hydrogen, halogen, —OR⁵, —OC(O)R⁵, —CN, —C(O)R⁵, —CO₂R⁵,            —C(O)NR⁵R^(5′), —NO₂, —NR⁵R^(5′), —NRC(O)R⁵, —NR⁵CO₂R^(5′),            —NR⁵S(O)₂R⁵—SR⁵, —S(O)R⁵, —S(O)₂R⁵, —S(O)₂NR⁵R^(5′), C₁₋₈            alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀            aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered            heterocyclyl; wherein        -   each R⁵ and R^(5′) may be independently selected from the            group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈            alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;    -   R⁴ is a substituted or unsubstituted C₁-C₈ alkyl, wherein when        substituted are substituted by the group consisting of halogen,        —OR⁵, —OC(O)R⁵, —CN, —C(O)R⁵, —CO₂R⁵, —C(O)NR⁵R^(5′), —NO₂,        —NR⁵R^(5′), —NRC(O)R⁵, —NR⁵CO₂R^(5′), —NR⁵S(O)₂R^(5′), —SR⁵,        —S(O)R⁵, —S(O)₂R⁵, —S(O)₂NR⁵R^(5′), C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₅₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 3- to 10-membered heterocyclyl; wherein        -   each R⁵ and R^(5′) may be independently selected from the            group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈            alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;    -   n is an integer from 0-3;    -   X^(a), X^(b) and X^(c) independently represent oxygen; sulfur;        substituted or unsubstituted nitrogen; or substituted or        unsubstituted carbon with the bonds between X^(a)—X^(b),        X^(b)—X^(b) and X^(a)—C (adjacent to nitrogen on pyrrolidine        ring) being single or optionally double bonds;    -   Z represents a substituted or unsubstituted 4 to 10-membered        ring which optionally contain up to three additional        heteroatoms; and    -   the bond between the two rings is in the (L) or optionally (D)        configuration.

In another embodiment of the invention, advantageous alkyl group for R¹and R² include linear or cyclic alkyl groups with 1-30 carbons whichinclude but are not limited to methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, orcyclodecyl.

In another embodiment of the invention, advantageous alkoxy group,alkoxycarbonyl group and aryl group for R, R¹ and R² are alkoxy groupswith 1-30 carbons which include but are not limited to methoxy, ethoxy,n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, cyclohexyloxy, phenyloxy;alkoxycarbonyl group with 1-30 carbons which include but are not limitedto methoxy-carbonyl, ethoxy-carbonyl, butoxy-carbonyl,pentyloxy-carbonyl and the aryl group with 6-30 carbon atoms whichinclude but are not limited to phenyl, 1-naphtyl, 2-naphthyl, 1-anthryl,2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, benzyl, or phenyl.

In another embodiment of the invention, advantageous alkyl groups,alkoxy groups, alkoxy-carbonyl groups and aryl groups for R, R¹ and R²include but are not limited to methyl, ethyl, n-propyl, n-butyl,cyclohexyl, cycloheptyl, as a alkyl group; phenyl, 1-naphthyl,2-naphthyl, 1-anthryl, 1-phenanthryl, benzyl as an aryl group; andadvantageous substituents include but are not limited to F, Cl, or Br asa halogen group; methoxy, ethoxy, propoxy, butoxy as an alkoxy group; orhydroxyl, carboxyl, acyl, amino, thio, or nitro group.

In another embodiment of the invention, advantageous ring systems for R¹and R² include but are not limited to cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane as an alkyl group;or benzene, naphthalene, anthracene, as an aromatic; or pyridine,pyrrolidine, piperidine, furan, pyran, tetrahydrofuran, tetrahydropyranas heteroaromatics.

In another embodiment of the invention, advantageous aldehydes offormula (I) include but are not limited to acetaldehyde, propylaldehyde,butylaldehyde, isobutylaldehyde, valeraldehyde, isovaleraldehyde,caproaldehyde, heptaldehyde, caprylic aldehyde, caprylic aldehyde,undecylaldehyde, lauraldehyde, tridecylaldehyde, pentadecylaldehyde,palmitic aldehyde, stearic aldehyde, squaric aldehyde.

In another embodiment of the invention, advantageous ketones of formula(II) include but are not limited to acetone, ethylmethylketone,propylmethylketone, isopropylmethylketone, butylmethylketone,diethylketone, diisopropylketone, 2-undecanone, fluoroacetone,chloroacetone, 2,4-pentadione, cyclobutanone, cyclopentanone,2-methylcyclohexanone, cyclodecanone, 2-norbornanone, 2-adamantanone,tetrahydropyrane-4-one, spiro[4,5]-1,4-dioxy-decane-8-one,1-benzylcarbonylpyperidine-4-one, 1-indanone, 2-indanone, α-tetralone,β-tetralone, 7-methoxy-2-tetralone, acetophenone, propiophenone,benzylphenone, dibenzylketone, 3,4-dimethylacetophenone, 2-acetophenone,2-choroloacetophenone.

In an advantageous embodiment of the invention, the aldehyde (formula(I)) or ketone (formula (II)) are selected from the group consisting of:

In another embodiment of the invention, advantageous nitroso compoundsof formula (III) include but are not limited to alkyl nitroso compoundswherein nitroso substitution is at the tertiary carbon, e.g.2-nitroso-isobutane, 2-nitroso-2-methylpentane. Advantageous substitutedaryl nitroso compounds include but are not limited to substitutednitrosobenzenes or 2-nitrosonaphthalene. Advantageous substituents foralkylnitroso catalysts include but are not limited to methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, alkoxy groupslike methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy,isobutoxy, t-butoxy, phenoxy, benzyloxy, phenethyloxy, or halogens likeF, Cl, Br, I. Advantageous substituents for nitrosobenzene include butare not limited to o-nitrosotoluene, m-nitrosotoluene, p-nitrosotoluene,3,5-dimethylnitrosobenzene, o-nitrosoethylbenzene, o-nitrosostyrene,o-nitrosoanisole, p-nitrosoanisole, o-nitrosophenol, m-nitrosophenol,o-fluoronitrosobenzene, m-fluoronitrosobenzene, p-fluoronitrosobenzene,o-chrolonitrosobenzene, m-chrolonitrosobenzene, p-chloronitrosobenzene,o-bromonitrosobenzene, m-bromonitrosobenzene, p-bromonitrosobenzene.

In an advantageous embodiment of the invention, the nitroso compound isPh-N═O.

In another embodiment of the invention, in the catalyst of formula (IV),the 5-membered ring bonded to the Z-ring is an aromatic ring. The5-membered aromatic heterocyclic ring includes but is not limited totetrazole, 1,2,3-triazole, 1,2,4-triazole, pyrazole, pyrazoline,imidazole, imidazoline, thiotriazoline and oxatriazoline.Advantageously, the five-membered ring is a tetrazole as disclosed informula (IVa) below:

The 5-10 membered heterocycle (Z-ring) bonded to the triazole ring informula IVa includes but is not limited to pyrrolidine, piperidine,hexamethyleneimine, heptamethyleneimine, oxazoline, oxazole, andsubstituents for these heterocycles which include but are not limited toalkyl groups like methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, or t-butyl groups, or alkoxy groups like methoxy or ethoxy.Smaller substituents are advantageous since a bulky ones would lower theyield of the process. The stereocenter adjacent to the nitrogen on theZ-ring is in the (L) or optionally (D) configuration.

Advantageously, the catalyst of formula (IV) includes but is not limitedto 5-(2′-pyrrolidinyl)-1H-1,2,3,4-tetrazole,5-(4H,5H-2′-oxazolyl)-1H-1,2,3,4-tetrazole,5-(2′-piperidinyl)-1H-1,2,3,4-tetrazole,5-benzo[c]-2′-piperidinyl-1H-1,2,3,4-tetrazole, 5-2% pyrolidinyl-1H-1,2,3-triazole, 5-2′-pyrrolidinyl-1H-1,2,4-triazole,2-2′-pyrrolidinyl-1H-imidazole, 5-2′-pyrrolidinyl-1H-imidazole,5-2′-pyrrolidinyl-1H,4H,5H-1,2,3,4-thiotriazoline,5-2′pyrrolidinyl-4H,5H-pyrazoline. Most advantageous is5-(2′-pyrrolidinyl)-1H-1,2,3,4-tetrazole as shown in structure (IVb):

The configuration of the stereogenic carbon adjacent to the nitrogen onthe pyrrolidine ring is the (L) or optionally (D) configuration.

In another embodiment of the invention, the enantioselectivity of theα-aminoxyketones and α-aminooxyaldehydes compounds produced by theprocess of the invention is greater than about 90% ee. Advantageously,enantioselectivity is greater than about 95% ee. More advantageously,enantioselectivity is greater than 99% ee.

In another embodiment of the invention, the purity of theα-aminooxyketones and α-aminooxyaldehydes compounds produced by theprocess of the invention is greater than about 90%. Advantageously,purity is greater than about 95%. More advantageously, purity is greaterthan 99%.

In another embodiment of the invention, the product yield of theα-aminooxyketones and α-aminooxyaldehydes compounds produced by theprocess of the invention is greater than about 80%. Advantageously,product yield is greater than about 85%. More advantageously, productyield is greater than 90%.

In another embodiment of the invention, the amount of catalyst offormula (IV) used in the process of the invention is less than about 10mol % but greater than 0 mol %. Advantageously, the amount of catalystof formula (IV) is the range of from about 2 mod % to about 5 mod %.More advantageously, the amount of catalyst of formula (IV) is about 5mol %.

In another embodiment of the invention, the molar equivalent ratio ofaldehyde (compound of formula (I)) or ketone (compound of formula (II))starting material to nitroso compound of formula (IIIa) or (IIIb) isbetween about 10:1 to about 1:2. Advantageously, the molar equivalentratio of aldehyde (compound of formula (I)) or ketone (compound offormula (II)) starting material to nitroso compound of formula (IIIa) or(IIIb) is between about 5:1 to about 1:1. More advantageously, the molarequivalent ratio of aldehyde (compound of formula (I)) or ketone(compound of formula (II)) starting material to nitroso compound offormula (IIIa) or (IIIb) is about 3:1.

In another embodiment of the invention, the solvent used in the processof the invention may be any solvent which facilitates the reaction ofthe aldehyde or ketone starting material and the nitroso compound in thepresence of the catalyst of formula (IV). Advantageous examples includebut are not limited to dimethylsulfoxide (DMSO), acetonitrile (MeCN),pyridine (Py) and dimethylformamide (DMF).

In another embodiment of the invention, corresponding α-hydroxyketonesbased on the α-aminooxyketones and aldehydes of the invention may besynthesized by treatment of an α-aminooxyketones or aldehydes with CuSO₄to in solution using known methods. Possible solvents include alcoholslike methanol and ethanol. The reaction temperature can be about 0°C.-25° C., and the reaction time can be about 3-10 hours.

The invention to synthesize α-aminooxyketones comprises reacting acarbonyl compound and a nitroso compound in the presence of the catalystwhich is shown in general structure (IV) or preferably tetrazolederivative (IVa or IVb). The amount of nitroso compound could be in arange of 2-4 equivalents and is preferably 2.5-3.5 equivalents versusthe carbonyl compound and the amount of catalyst which is shown inscheme (III) could be 1-10 mol % and preferably 2-20 mol %. The solventcould be water, chloroalkane like dichloromethane, chloroform,dichloroethane, chlorobenzene, hydrocarbon aromatics like benzene,toluene, xylene, aliphatic hydrocarbons like cyclohexane, n-hexane,n-heptane, esters like ethylacetate, nitriles like acetonitrile ordimethylsulfoxide and preferably dimethylsufoxide or acetonitrile. Theamount of the solvent could be 15-30 volumes but the reaction can beperformed without solvent. The reaction temperature could be 0-50° C.and preferably 20-30° C. but the reaction can be performed at roomtemperature. The reaction time can be 30 minutes to 3 hours, and forexample the reaction can be performed in open air with stirring for 1hour. The reaction is very mild and furthermore, water will not inhibitthe reaction, so there is no need for dehydrating the starting materialand catalyst and the reaction is easy to control. After the reaction iscomplete, the product can be extracted with ethyl acetate and then driedand purified through known methods.

The reaction between the proline-derived catalysts used in the presentinvention and an aldehyde or ketone is suspected to yield an enanmineintermediate. We postulated that the O-nitroso Aldol reactions of thepresent invention also involve the intermediacy of an enamine. To testthis hypothesis, a simple enamine derived from pyrrolidine andcyclohexane was reacted with nitrosobenzene. The schematic of thisreaction is displayed in FIG. 1. Reaction of nitrosobenzene withpyrrolidine enamine in benzene at 0° C. generated a new intermediate 1,which was converted to the second intermediate 2 by the exposure ofacetic acid. The intermediate 2 was able to be transformed to theaminooxy ketone after usual work-up (FIG. 1). Various solvents andtemperature combination were examined for this transformation, and DMSOemerged as the most suitable solvent to afford aminooxy ketone withoutproduction of azoxy dimmer byproduct. ¹H NMR study in DMSO-d₆ revealed adownfield shift of enamine olefin proton (J=3.9 Hz) from 54.1 to 4.4ppm, one proton broad singlet at 58.2 ppm due to the aminooxy NH, andone proton triplet (J=4.5 Hz) at pyrrolidine α-position at δ4.3 ppm,which indicate the formation of the intermediate 1 (32). After treatmentwith acetic acid, complete conversion to a single new species isobserved. This is assigned as the iminium salt 2 (33, 34); thesignificant downfield shift from δ4.3 to 5.3 ppm (α-proton of iminiumgroup) and disappearance of δ4 ppm triplet (35). After work-up, theiminium salt 2 can be hydrized to α-aminooxy ketone.

Interestingly, in the O-nitroso aldol reactions, aldehyde substratesafford products with the opposite configuration of those of ketonesubstrates. This observation suggests the possibility of differenttransition states depending on the choice of starting carbonylcompounds. Proposed transition states that account for this observationare displayed in FIG. 2. A possible explaination that accounts for theobserved stereochemistry is that the bulkier ketone substrate will beforced to adopt a conformation which limits steric interactions in thetransition state. The less bulky aldehyde will be freer to adopt aconformation which maximizes the electronic interactions in thetransition state. While not wishing to be bound by theory, the reactionof nitrosobenzene may proceed from the same side of tetrazole (orcarboxylic acid) by either direct activation of nitrosobenzene by acidicproton (10 a, 10 b) or indirect route via amine-nitrosobenzenecomplexation followed by rearrangement (10 a′, 10 b′). The proposedtransition states for the O-nitroso aldol reaction of ketones (left) andaldehydes (right) is shown below:

The invention also provides a method for performing highlyenantioselective O-nitoso Aldol/Michael reactions betweenα,β-unsaturated ketones and nitroso substrates catalyzed by aproline-derived compound. More specifically, the catalytic nitrosoaldol/Michael reaction provides a means of generating enantioenrichedbicyclo ketones containing a nitrogen amd an oxygen atom. Themethodology affords a product bicyclo ketone which is not normallyavailable from running a classical hetero Diels-Alder reaction.

The process of making reaction products from cyclic α,β-unsaturatedketone substrates and nitroso substrates (also referred to as acatalytic asymmetric O-nitroso Aldol/Michael Reaction) may berepresented as follows:

This reaction provides a method for the catalytic asymmetric synthesisof a heterocyclic product that has the opposite regiochemistry of thisproduct formed in a hetero Diels-Alder reaction. The hetero-Diels-Alderproduct is shown below:

In one embodiment, the cyclic α,β-unsaturated ketone substrate may berepresented by formulae (V), (VI), (VII), (VIII), (IX), or (X):

where R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, X¹, X², X³, X⁴, X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰and n are as defined below.

In one embodiment, the cyclic α,β-unsaturated ketone substrate may havea structure (V):

where:

-   -   each R⁶ may represent a substituent independently selected from        the group consisting of hydrogen, halogen, —OR^(i), —OC(O)R^(i),        —CN, —C(O)R^(i), —CO₂R^(i), —C(O)NR^(i)R^(ii), —NO₂,        —NR^(i)R^(ii), —NR^(i)C(O)R^(ii), —NR^(i)CO₂R^(ii),        —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(i), —S(O)₂R^(i),        —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C2-8 alkenyl, C2-8 alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to        10-membered heterocyclyl;    -   each X¹ may independently represent —CR¹²R¹³—, —NR¹²—, —O—, or        —S—;        -   R¹² and R¹³ may represent substituents independently            selected from the group consisting of hydrogen, halogen,            —OR^(i), —OC(O)R^(i), —CN, —C(O)R^(i), —CO₂R^(i),            —C(O)NR^(i)R^(ii), —NO₂, —NR^(i)R^(ii), —NR^(i)C(O)R^(ii),            —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(ii),            —S(O)₂R^(i), —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C₂₋₈ alkenyl,            C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;        -   each R¹² and R¹³, together with the atom to which they are            attached, may form a 5-, 6- or 7-membered heterocyclic ring;            and    -   X² may represent —C— or —S—;    -   each R^(i) and R^(ii) may independently selected from the group        consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and        3- to 10-membered heterocyclyl.        In another embodiment, the cyclic α,β-unsaturated ketone        substrate may have a structure (V) wherein:

each R⁶ may represent a substituent independently selected from thegroup consisting of hydrogen, C₁₋₈ alkyl, C₆ aryl and a 5-memberedheterocyclyl,

each X¹ may independently represent —CR¹²R¹³—;

-   -   R¹² and R¹³ may represent a substituent independently selected        from the group consisting of hydrogen, C₁₋₈ alkyl, C₆ aryl and a        5-membered heterocyclyl,    -   X² may represent —C—.        In one embodiment, the cyclic α,β-unsaturated ketone substrate        may have a structure (VI):

where:

-   -   each R⁷ may represent a substituent independently selected from        the group consisting of hydrogen, halogen, —OR^(i), —OC(O)R^(i),        —CN, —C(O)R^(i), —CO₂R^(i), —C(O)NR^(i)R^(ii), —NO₂,        —NR^(i)C(O)R^(ii), —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii),        —SR^(i), —S(O)R^(i), —S(O)₂R^(i), —S(O)₂NR^(i)R^(ii), C₁₋₈        alkyl, C2-8 alkenyl, C2-8 alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl,        5- to 10-membered heteroaryl, and 3- to 10-membered        heterocyclyl;    -   each X³ may independently represent —CR¹²R¹³—, —NR¹²—, —O—, or        —S—;        -   R¹² and R¹³ may represent substituents independently            selected from the group consisting of hydrogen, halogen,            —OR^(i), —OC(O)R^(i), —CN, —C(O)R^(i), CO₂R^(i),            —C(O)NR^(i)R^(ii), —NO₂, —NR^(i)C(O)R^(ii),            —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii), —S(O)R^(ii),            —S(O)₂R^(i), —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C₂₋₈ alkenyl,            C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;        -   each R¹² and R¹³, together with the atom to which they are            attached, may form a 5-, 6- or 7-membered heterocyclic ring;            and    -   X⁴ may represent —C— or —S—;    -   each R^(i) and R^(ii) may independently selected from the group        consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and        3- to 10-membered heterocyclyl.        In another embodiment, the cyclic α,β-unsaturated ketone        substrate may have a structure (VI) wherein:

each R⁷ may represent a substituent independently selected from thegroup consisting of hydrogen, C₁₋₈ alkyl, C₆ aryl and a 5-memberedheterocyclyl,

each X³ may independently represent —CR¹²R¹³—;

-   -   R¹² and R¹³ may represent a substituent independently selected        from the group consisting of hydrogen, C₁₋₈ alkyl, C₆ aryl and a        5-membered heterocyclyl,    -   X⁴ may represent —C—.        In one embodiment, the cyclic α,β-unsaturated ketone substrate        may have a structure (VII):

where,

-   -   each R⁸ may independently represent a substituent selected from        the group consisting of hydrogen, halogen, —OR^(c), —OC(O)R^(c),        —CN, —C(O)R^(c), —CO₂R^(c), —C(O)NR^(c)R^(d), —NO₂,        —NR^(c)R^(d), —NR^(c)C(O)R^(d), —NR^(c)CO₂R^(d),        —NR^(c)S(O)₂R^(d), —SR^(c), —S(O)R^(c), —S(O)₂R^(c),        —S(O)₂NR^(c)R^(d), C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to        10-membered heterocyclyl;    -   n may be 0, 1, 2, or 3; and    -   each R^(c) and R^(d) may be independently selected from the        group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈        alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 3- to 10-membered heterocyclyl.        In another embodiment, the cyclic α,β-unsaturated ketone        substrate may have a structure (VII) wherein:

each R⁸ may represent a substituent independently selected from thegroup consisting of hydrogen, C₁₋₈ alkyl, C₆ aryl and 5-memberedheterocyclyl; and

n is 0 or 1.

In one embodiment, the cyclic α,β-unsaturated ketone substrate may havea structure (VIII):

where:

-   -   each R⁹ may represent a substituent independently selected from        the group consisting of hydrogen, halogen, —OR, —OC(O)R^(i),        —CN, —C(O)R^(i), —CO₂R^(i), —C(O)NR^(i)R^(ii), —NO₂,        —NR^(i)C(O)R^(ii), —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii),        —SR^(i), —S(O)R^(i), —S(O)₂R^(i), —S(O)₂NR^(i)R^(ii), C₁₋₈        alkyl, C2-8 alkenyl, C2-8 alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl,        5- to 10-membered heteroaryl, and 3- to 10-membered        heterocyclyl;    -   each X⁵ may independently represent —CR¹²R¹³—, —NR¹²—, —O—, or        —S—;        -   R¹² and R¹³ may represent substituents independently            selected from the group consisting of hydrogen, halogen,            —OR^(i), —OC(O)R^(i), —CN, —C(O)R^(i), CO₂R^(i),            —C(O)NR^(i)R^(ii), —NO₂, —NR^(i)R^(ii), —NR^(i)C(O)R^(ii),            —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(ii),            —S(O)₂R^(i), —S(O)₂NR^(i)R^(ii), C₁₋₈-alkyl, C₂₋₈ alkenyl,            C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;        -   each R¹² and R¹³, together with the atom to which they are            attached, may form a 5-, 6- or 7-membered heterocyclic ring;            and    -   X⁶ may represent —C— or —S—;    -   each R^(i) and R^(ii) may independently selected from the group        consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and        3- to 10-membered heterocyclyl.        In another embodiment, the cyclic α,β-unsaturated ketone        substrate may have a structure (VIII) wherein:

each R⁹ may represent a substituent independently selected from thegroup consisting of hydrogen, C₁₋₈ alkyl, C₆ aryl and a 5-memberedheterocyclyl,

each X⁵ may independently represent —CR¹²R¹³—;

-   -   R¹² and R¹³ may represent a substituent independently selected        from the group consisting of hydrogen, C₁₋₈ alkyl, C₆ aryl and a        5-membered heterocyclyl,

X⁶ may represent —C—.

In one embodiment, the cyclic α,β-unsaturated ketone substrate may havea structure (IX):

where:

-   -   each R¹⁰ may represent a substituent independently selected from        the group    -   consisting of hydrogen, halogen, —OR^(i), —OC(O)R^(i), —CN,        —C(O)R^(i), —CO₂R^(i), —C(O)NR^(i)R^(ii), —NO₂, —NR^(i)R^(ii),        —NR^(i)C(O)R^(ii), —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii),        —SR^(i), —S(O)R^(i), —S(O)₂R^(i), —S(O)₂NR^(i)R^(ii), C₁₋₈        alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl,        5- to 10-membered heteroaryl, and 3- to 10-membered        heterocyclyl;    -   each X⁷ may independently represent —CR¹²R¹³—, —NR¹²—, —O—, or        —S—;        -   R¹² and R¹³ may represent substituents independently            selected from the group consisting of hydrogen, halogen,            —OR^(i), —OC(O)R^(i), —CN, —C(O)R^(i), —CO₂R^(i),            —C(O)NR^(i)R^(ii), —NO₂, —NR^(i)R^(ii), —NR^(i)C(O)R^(ii),            —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(ii),            —S(O)₂R^(i), —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C₂₋₈ alkenyl,            C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;        -   each R¹² and R¹³, together with the atom to which they are            attached, may form a 5-, 6- or 7-membered heterocyclic ring;            and    -   X⁸ may represent —C— or —S—;    -   each R^(i) and R^(ii) may independently selected from the group        consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and        3- to 10-membered heterocyclyl.        In another embodiment, the cyclic α,β-unsaturated ketone        substrate may have a structure (IX) wherein:

each R¹⁰ may represent a substituent independently selected from thegroup consisting of hydrogen, C₁₋₈ alkyl, C₆ aryl and a 5-memberedheterocyclyl,

each X⁷ may independently represent —CR¹²R¹³—;

-   -   R¹² and R¹³ may represent a substituent independently selected        from the group consisting of hydrogen, C₁₋₈ alkyl, C₆ aryl and a        5-membered heterocyclyl,

X⁸ may represent —C—.

In one embodiment, the cyclic α,β-unsaturated ketone substrate may havea structure (X):

where:

-   -   each R¹¹ may represent a substituent independently selected from        the group consisting of hydrogen, halogen, —OR^(i), —OC(O)R^(i),        —CN, —C(O)R^(i), —CO₂R^(i), —C(O)NR^(i)R^(ii), —NO₂,        —NR^(i)R^(ii), —NR^(i)C(O)R^(ii), —NR^(i)CO₂R^(ii),        —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(i), —S(O)₂R^(i),        —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C2-8 alkenyl, C2-8 alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to        10-membered heterocyclyl;    -   X⁹ may represent —CR¹²R¹³—, —NR¹²—, —O—, or —S—;        -   R¹² and R¹³ may represent substituents independently            selected from the group consisting of hydrogen, halogen,            —OR^(i), —OC(O)R^(i), —CN, —C(O)R^(i), —CO₂R^(i),            —C(O)NR^(i)R^(ii), —NO₂, —NR^(i)R^(ii), —NR^(i)C(O)R^(ii),            —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(ii),            —S(O)₂R^(i), —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C₂₋₈ alkenyl,            C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;        -   each R¹² and R¹³, together with the atom to which they are            attached, may form a 5-, 6- or 7-membered heterocyclic ring;            and    -   X¹⁰ may represent —C— or —S—;    -   each R^(i) and R^(ii) may independently selected from the group        consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and        3- to 10-membered heterocyclyl.        In another embodiment, the cyclic α,β-unsaturated ketone        substrate may have a structure (X) wherein:

each R¹¹ may represent a substituent independently selected from thegroup consisting of hydrogen, C₁₋₈ alkyl, C₆ aryl and a 5-memberedheterocyclyl,

each X⁹ may independently represent —CR¹²R¹³—;

-   -   R¹² and R¹³ may represent a substituent independently selected        from the group consisting of hydrogen, C₁₋₈ alkyl, C₆ aryl and a        5-membered heterocyclyl,

X¹⁰ may represent —C—.

In one embodiment, the cyclic α,β-unsaturated ketone substrate may beselected from the group consisting of:

In one embodiment, the nitroso substrate may be represented by thestructure XI.

where:

-   -   R¹⁴ may represent 1 to 5 substituents each independently        selected from the group consisting of hydrogen, halogen,        —OR^(iii), —OC(O)R^(iii), —CN, —C(O)R^(iii), —CO₂R^(iii),        —C(O)NR^(iii)R^(iv), —NO₂, —NR^(iii)R^(iv), —NR^(iii)C(O)R^(iv),        —NR^(iii)CO₂R^(iv), —NR^(iii)S(O)₂R^(iv), —SR^(iii),        —S(O)R^(iii), —S(O)₂R^(iii), —S(O)₂NR^(iii)R^(iv), C₁₋₈ alkyl,        C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, and 3- to 10-membered heterocyclyl;        -   each R^(iii) and R^(iv) may be independently selected from            the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈            alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl.

In another embodiment of the invention, the nitroso substrate may berepresented by the structure (XI) wherein:

R¹⁴ may represent 1 to 5 substituents each independently selected fromthe group consisting of hydrogen, halogen and C₁₋₈ alkyl.

In another embodiment of the invention, the nitroso substrate may beselected from the group consisting of:

In one embodiment, the proline-based catalyst used in the O-nitrosoAldol/Michael reaction may be represented by the following structure(XII), wherein the stereocenter on the pyrrolidine ring (alpha to thenitrogen) is in the (L) or optionally (D) configuration.

The R¹⁵ substituent may be selected from the group consisting of:

The R¹⁶ may be a substituent selected from the group consisting ofhydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

In an advantageous embodiment of the invention, the proline-basecatalyst may be selected from the group consisting of:

In another embodiment, the enantioselective O-nitroso Aldol/Michaelreaction is carried out in the presence of a catalyst with the followingformula:

where:

-   X^(a), X^(b) and X^(c) independently represent oxygen; sulfur;    substituted or unsubstituted nitrogen; or substituted or    unsubstituted carbon with the bonds between X^(a)—X^(b), X^(b)—X^(c)    and X^(a)—C (alpha to nitrogen) being single or optionally double    bonds;    -   Z represents a substituted or unsubstituted 4 to 10-membered        ring which optionally contain up to three additional        heteroatoms; and    -   the bond between the two rings is in the (L) or optionally (D)        configuration.

In another embodiment of the invention, in the catalyst of formula (IV),the 5-membered ring bonded to the Z-ring is an aromatic ring. The5-membered aromatic heterocyclic ring includes but is not limited totetrazole, 1,2,3-triazole, 1,2,4-triazole, pyrazole, pyrazoline,imidazole, imidazoline, thiotriazoline and oxatriazoline.Advantageously, the five-membered ring is a tetrazole as disclosed informula (IVa) below:

The 5-10 membered heterocycle (Z-ring) bonded to the triazole ring informula IVa includes but is not limited to pyrrolidine, piperidine,hexamethyleneimine, heptamethyleneimine, oxazoline, oxazole, andsubstituents for these heterocycles which include but are not limited toalkyl groups like methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, or t-butyl groups, or alkoxy groups like methoxy or ethoxy.Smaller substituents are advantageous since bulky ones would lower theyield of the process. The stereocenter alpha to the nitrogen on theZ-ring is in the (L) or optionally (D) configuration.

Advantageously, the catalyst of formula (IV) includes but is not limitedto 5-(2′-pyrrolidinyl)-1H-1,2,3,4-tetrazole,5-(4H,5H-2′-oxazolyl)-1H-1,2,3,4-tetrazole,5-(2′-piperidinyl)-1H-1,2,3,4-tetrazole,5-benzo[c]-2′-piperidinyl-1H-1,2,3,4-tetrazole,5-2′-pyrrolidinyl-1H-1,2,3-triazole, 5-2′-pyrrolidinyl1H-1,2,4-triazole,2-2′-pyrrolidinyl-1H-imidazole, 5-2′-pyrrolidinyl-1H-imidazole,5-2′-pyrrolidinyl-1H,4H,5H-1,2,3,4-thiotriazoline,5-2′pyrrolidinyl-4H,5H-pyrazoline. Most advantageous is5-(2′-pyrrolidinyl)-1H-1,2,3,4-tetrazole as shown in structure (IVb):

The configuration of the stereogenic carbon alpha to the nitrogen on thepyrrolidine ring is the (L) or optionally (D) configuration.

The proline-based catalysts of the invention may be obtained via themethods and processes described above in the “Detailed Description forthe Process of Making α-aminooxyketone/α-aminooxyaldehyde andα-hydroxyketone/α-hydroxyaldehyde” and “Examples for the Process ofMaking α-aminooxyketone/α-aminooxyaldehyde andα-hydroxyketone/α-hydroxyaldehyde” which is incorporated herein byreference.

In one embodiment, the heterocyclic product formed by theenantioselective O-nitroso/aldol reaction between the compound offormula V and the compound of formula XI is represented by the followingstructure (XIII):

where:

-   -   each R⁶ may represent a substituent independently selected from        the group consisting of hydrogen, halogen, —OR^(i), —OC(O)R^(i),        —CN, —C(O)R^(i), —CO₂R^(i), —C(O)NR^(i)R^(ii), —NO₂,        —NR^(i)R^(ii), —NR^(i)C(O)R^(ii), —NR^(i)CO₂R^(ii),        —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(i), —S(O)₂R^(i),        —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C2-8 alkenyl, C2-8 alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to        10-membered heterocyclyl;    -   each X¹ may independently represent —CR¹²R¹³—, —NR¹²—, —O—, or        —S—;        -   R¹² and R¹³ may represent substituents independently            selected from the group consisting of hydrogen, halogen,            —OR^(i), —OC(O)R^(i), —CN, —C(O)R^(i), —CO₂R^(i),            —C(O)NR^(i)R^(ii), —NO₂, —NR^(i)R^(ii), —NR^(i)C(O)R^(ii),            —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(ii),            —S(O)₂R^(i), —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C₂₋₈ alkenyl,            C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;        -   each R¹² and R¹³, together with the atom to which they are            attached, may form a 5-, 6- or 7-membered heterocyclic ring;            and    -   X² may represent —C— or —S—;    -   each R^(i) and R^(iv) may independently selected from the group        consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and        3- to 10-membered heterocyclyl.    -   R¹⁴ may represent 1 to 5 substituents each independently        selected from the group consisting of hydrogen, halogen,        —OR^(iii), —OC(O)R^(iii), —CN, —C(O)R^(iii), —CO₂R^(iii),        —C(O)NR^(iii)R^(iv), —NO₂, —NR^(iii)R^(iv), —NR^(iii)C(O)R^(iv),        —NR^(iii)O₂R^(iv), —NR^(iii)S(O)₂R^(iv), —SR^(iii),        —S(O)R^(iii), —S(O)₂R^(iii), —S(O)₂NR^(iv), C₁₋₈ alkyl, C2-8        alkenyl, C2-8 alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, and 3- to 10-membered heterocyclyl;        -   each R^(iii) and R^(iv) may be independently selected from            the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈            alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl.

In another embodiment, the heterocyclic product formed by theenantioselective O-nitroso/aldol reaction between the compound offormula VI and the compound of formula XI is represented by thefollowing structure (XIV):

where:

-   -   each R⁷ may represent a substituent independently selected from        the group consisting of hydrogen, halogen, —OR^(i), —OC(O)R^(i),        —CN, —C(O)R^(i), —CO₂R^(i), —C(O)NR^(i)R^(ii), —NO₂,        —NR^(i)R^(ii), —NR^(i)C(O)R^(ii), —NR^(i)CO₂R^(ii),        —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(i), —S(O)₂R^(i),        —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C2-8 alkenyl, C2-8 alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to        10-membered heterocyclyl;    -   each X³ may independently represent —CR¹²R¹³—, —NR²—, —O—, or        —S—;        -   R¹² and R¹³ may represent substituents independently            selected from the group consisting of hydrogen, halogen,            —OR^(i), —OC(O)R^(i), —CN, —C(O)R^(i), —CO₂R^(i),            —C(O)NR^(i)R^(ii), —NO₂, —NR^(i)R^(ii), —NR^(i)C(O)R^(ii),            —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(ii),            —S(O)₂R^(ii), —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C₂₋₈ alkenyl,            C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;        -   each R¹² and R¹³, together with the atom to which they are            attached, may form a 5-, 6- or 7-membered heterocyclic ring;            and    -   X⁴ may represent —C— or —S—;    -   each R^(i) and R^(ii) may independently selected from the group        consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and        3- to 10-membered heterocyclyl.    -   R¹⁴ may represent 1 to 5 substituents each independently        selected from the group consisting of hydrogen, halogen,        —OR^(iii), —OC(O)R^(iii), —CN, —C(O)R^(iii), —CO₂R^(iii),        —C(O)NR^(iii)R^(iv), —NO₂, —NR^(iii)R^(iv), —NR^(iii)C(O)R^(iv),        —NR^(iii)CO₂R^(iv), —NR^(iii)S(O)₂R^(iv), —SR^(iii),        —S(O)R^(iii), —S(O)₂R^(iii), —S(O)₂NR^(iii)R^(iv), C₁₋₈ alkyl,        C2-8 alkenyl, C2-8 alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, and 3- to 10-membered heterocyclyl;    -   each R^(iii) and R^(iv) may be independently selected from the        group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to        10-membered heterocyclyl

In another embodiment, the heterocyclic product formed by theenantioselective O-nitroso/aldol reaction between the compound offormula VII and the compound of formula XI is represented by thefollowing structure (XV):

where:

-   -   each R⁸ may independently represent a substituent selected from        the group consisting of hydrogen, halogen, —OR^(c), —OC(O)R^(c),        —CN, —C(O)R^(c), —CO₂R^(c), —C(O)NR^(c)R^(d), —NO₂,        —NR^(c)R^(d), —NR^(c)C(O)R^(d), —NR^(c)CO₂R^(d),        —NR^(c)S(O)₂R^(d), —SR^(c), —S(O)R^(c), —S(O)₂R^(c),        —S(O)₂NR^(c)R^(d), C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to        10-membered heterocyclyl;    -   n may be 0, 1, 2, or 3; and    -   each R^(c) and R^(d) may be independently selected from the        group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈        alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 3- to 10-membered heterocyclyl.        -   R¹⁴ may represent 1 to 5 substituents each independently            selected from the group consisting of hydrogen, halogen,            —OR^(iii), —OC(O)R^(iii), —CN, —C(O)R^(iii), —CO₂R^(iii),            —C(O)NR^(iii)R^(iv), —NO₂, —NR^(iii)R^(iv),            —NR^(iii)C(O)R^(iv), —NR^(iii)CO₂R^(iv),            —NR^(iii)S(O)₂R^(iv), —SR^(iii), —S(O)R^(iii),            —S(O)₂R^(iii), —S(O)₂NR^(iii)R^(iv), C₁₋₈ alkyl, C2-8            alkenyl, C2-8 alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to            10-membered heteroaryl, and 3- to 10-membered heterocyclyl;    -   each R^(iii) and R^(iv) may be independently selected from the        group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to        10-membered heterocyclyl

In another embodiment, the heterocyclic product formed by theenantioselective O-nitroso/aldol reaction between the compound offormula VIII and the compound of formula XI is represented by thefollowing structure (XVI):

where:

-   -   each R⁹ may represent a substituent independently selected from        the group consisting of hydrogen, halogen, —OR^(i), —OC(O)R^(i),        —CN, —C(O)R^(i), —CO₂R^(i), —C(O)NR^(i)R^(ii), —NO₂,        —NR^(i)R^(ii), —NR^(i)C(O)R^(ii), —NR^(i)CO₂R^(ii),        —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(i), —S(O)₂R^(i),        —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C2-8 alkenyl, C2-8 alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to        10-membered heterocyclyl;    -   each X⁵ may independently represent —CR¹²R¹³—, —NR²—, —O—, or        —S—;        -   R¹² and R¹³ may represent substituents independently            selected from the group consisting of hydrogen, halogen,            —OR^(i), —OC(O)R^(i), —CN, —C(O)R^(i), —CO₂R^(i),            —C(O)NR^(i)R^(ii), —NO₂, —NR^(i)R^(ii), —NR^(i)C(O)R^(ii),            —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(ii),            —S(O)₂R^(i), —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C₂₋₈ alkenyl,            C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;        -   each R¹² and R¹³, together with the atom to which they are            attached, may form a 5-, 6- or 7-membered heterocyclic ring;            and    -   X⁶ may represent —C— or —S—;    -   R¹⁴ may represent 1 to 5 substituents each independently        selected from the group consisting of hydrogen, halogen,        —OR^(iii), —OC(O)R^(iii), —CN, —C(O)R^(iii), —CO₂R^(iii),        —C(O)NR^(iii)R^(iv), —NO₂, —NR^(iii)R^(iv), —NR^(iii)C(O)R^(iv),        —NR^(iii)CO₂R^(iv), —NR^(iii)S(O)₂R^(iv), —SR^(iii),        —S(O)R^(iii), —S(O)₂R^(iii), —S(O)₂NR^(iii)R^(iv), C₁₋₈ alkyl,        C2-8 alkenyl, C2-8 alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, and 3- to 10-membered heterocyclyl;    -   each R^(iii) and R^(iv) may be independently selected from the        group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₄₈ alkynyl,        C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and        3- to 10-membered heterocyclyl.

In another embodiment, the heterocyclic product formed by theenantioselective O-nitroso/aldol reaction between the compound offormula IX and the compound of formula XI is represented by thefollowing structure (XVII):

where:

-   -   each R¹⁰ may represent a substituent independently selected from        the group consisting of hydrogen, halogen, —OR^(i), —OC(O)R^(i),        —CN, —C(O)R^(i), —CO₂R^(i), —C(O)NR^(i)R^(ii), —NO₂,        —NR^(i)R^(ii), —NR^(i)C(O)R^(ii), —NR^(i)CO₂R^(ii),        —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(i), —S(O)₂R^(i),        —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C2-8 alkenyl, C2-8 alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to        10-membered heterocyclyl;    -   each X⁷ may independently represent —CR¹²R¹³—, —NR²—, —O—, or        —S—;        -   R¹² and R¹³ may represent substituents independently            selected from the group consisting of hydrogen, halogen,            —OR^(i), —OC(O)R^(i), —CN, —C(O)R^(i), —CO₂R^(i),            —C(O)NR^(i)R^(ii), —NO₂, —NR^(i)R^(ii), —NR^(i)C(O)R^(ii),            —NR^(i)CO₂R^(ii), —NR^(i)S(O)₂R^(ii), —SR^(i), —S(O)R^(ii),            —S(O)₂R^(ii), —S(O)₂NR^(i)R^(ii), C₁₋₈ alkyl, C₂₋₈ alkenyl,            C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, and 3- to 10-membered heterocyclyl;        -   each R¹² and R¹³, together with the atom to which they are            attached, may form a 5-, 6- or 7-membered heterocyclic ring;            and    -   X⁸ may represent —C— or —S—;    -   each R^(i) and R^(ii) may independently selected from the group        consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and        3- to 10-membered heterocyclyl.    -   R¹⁴ may represent 1 to 5 substituents each independently        selected from the group consisting of hydrogen, halogen,        —OR^(iii), —OC(O)R^(iii), —CN, —C(O)R^(iii), —CO₂R^(iii),        —C(O)NR^(iii)R^(iv), —NO₂, —NR^(iii)R^(iv), —NR^(iii)C(O)R^(iv),        —NR^(iii)CO₂R^(iv), —NR^(iii)S(O)₂R^(iv), —SR^(iii),        —S(O)R^(iii), —S(O)₂R^(iii), —S(O)₂NR^(iii)R^(iv), C₁₋₈ alkyl,        C2-8 alkenyl, C2-8 alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, and 3- to 10-membered heterocyclyl;    -   each R^(iii) and R^(iv) may be independently selected from the        group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to        10-membered heterocyclyl.

In another embodiment of the invention, the enantioselectivity of theα-aminooxyketones and α-aminooxyaldehydes compounds produced by theprocess of the invention is greater than about 90% ee. Advantageously,enantioselectivity is greater than about 95% ee. More advantageously,the enantioselectivity is greater than 99% ee.

In another embodiment of the invention, the amount of proline-basedcatalyst used in the process of the invention is less than about 40 mol% but greater than 0 mol %. Advantageously, the amount of proline basedcatalyst is the range of from about 10 mol % to about 30 mol %. Moreadvantageously, the amount of proline-based catalyst is about 20 mol %.

In another embodiment of the invention, the molar ratio of the amount ofnitroso compound to α,β-unsaturated cyclic ketone (enone) is from about10:1 to about 0.5:1. Advantageously, the molar ratio of the amount ofnitroso compound to α,β-unsaturated cyclic ketone (enone) is from about4:1 to about 1:1. More advantageously, the molar ratio of the amount ofnitroso compound to α,β-unsaturated cyclic ketone (enone) is from about2:1.

The invention also encompasses pharmaceutical compositions that maycomprise the α-aminoxyketones, α-hydroxyketones and cyclic α,βunsaturated ketones described herein. In an advantageous embodiment, theinvention encompasses anti-cancer or anti-viral compositions that maycomprise α-aminoxyketones, α-hydroxyketones and cyclic α,β unsaturatedketones, or derivatives thereof, and methods for administering the same.

In one embodiment, the α-aminooxyketones of the present invention may besubstituted for its natural equivalent. Such substitutions will beapparent to one of skill in the art. In another embodiment, theα-aminooxyketones of the present invention may be substituted forα-hydroxyketones and their equivalents thereof. Such substitutions willbe apparent to one of skill in the art. In another embodiment, theα-hydroxyketones of the present invention may be substituted for itsnatural aldose equivalent. Such substitutions will be apparent to one ofskill in the art.

The compounds of the invention may be useful for treating or preventinga variety of cancers, including, but not limited to, leukemias,including but not limited to acute leukemia, acute lymphocytic leukemia,acute myelocytic leukemia, myeloblastic, promyelocytic, myelomonocytic,monocytic, erythroleukemia, chronic leukemia, chronic myelocytic,(granulocytic) leukemia, chronic lymphocytic leukemia, Polycythemiavera, Lymphomas including but not limited to Hodgkin's disease,non-Hodgkin's disease, Multiple myeloma, Waldenstrom'smacroglobulinemia, Heavy chain disease, Solid tumors including but notlimited to sarcomas and carcinomas, fibrosarcoma, myxosarcoma,liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, prostate cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterinecancer, testicular tumor, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, and neuroblastomaretinoblastoma.

The compounds of the invention may be useful for treating or preventinga variety of viral infections, including, but not limited to thosecaused by infection with hepatitis B, hepatitis C, rotavirus, humanimmunodeficiency virus type I (HIV-I), human immunodeficiency virus typeII (HIV-II), human T-cell lymphotropic virus type I (HTLV-I), humanT-cell lymphotropic virus type II (HTLV-II), AIDS, DNA viruses such ashepatitis type B and hepatitis type C virus; parvoviruses, such asadeno-associated virus and cytomegalovirus; papovaviruses such aspapilloma virus, polyoma viruses, and SV40; adenoviruses; herpes virusessuch as herpes simplex type I (HSV-I), herpes simplex type II (HSV-II),and Epstein-Barr virus; poxviruses, such as variola (smallpox) andvaccinia virus; and RNA viruses, such as human immunodeficiency virustype I (HIV-I), human immunodeficiency virus type II (HIV-II), humanT-cell lymphotropic virus type I (HTLV-I), human T-cell lymphotropicvirus type II (HTLV-II), influenza virus, measles virus, rabies virus,Sendai virus, picornaviruses such as poliomyelitis virus,coxsackieviruses, rhinoviruses, reoviruses, togaviruses such as rubellavirus (German measles) and Semliki forest virus, arboviruses, andhepatitis type A virus.

In an advantageous embodiment, the compounds of the present invention,or a derivative thereof, may be useful as an antiviral against orthopoxviruses, such as, but not limited to, smallpox, monkeypox and cowpox(see, e.g., Chu et al., Bioorg Med Chem Lett. 2003 Jan. 6; 13(1):9-12).In another advantageous embodiment, the cyclic α,β unsaturated ketonesof the present invention, or a derivative thereof, may be used in thesynthesis of nucleosides, nucleotides or derivatives thereof that may beused as antiviral therapeutic agents (see, e.g., Jin & Chu, NucleosidesNucleotides Nucleic Acids. 2003 May-August; 22(5-8):771-3).

The compounds of the invention may be useful for treating or preventingseveral types of inflammation, including, but not limited to, eczema,inflammatory bowel disease, rheumatoid arthritis, asthma, psoriasis,ischemia/reperfusion injury, ulcerative colitis and acute respiratorydistress syndrome. In an advantageous embodiment, the compounds of thepresent invention, or a derivative thereof, may be used as an inhibitorof interleukin-1 biosynthesis (see, e.g., Batt et al., J Med Chem. 1993May 14; 36(10):1434-42).

In another embodiment, the compounds of the invention are useful fortreating or preventing ulcers. For example, urease inhibitors haverecently attracted much attention as potential new anti-ulcer drugs(see, e.g., Amtul et al., Curr Med Chem. 2002 July; 9(14):1323-48).Accordingly, the compounds of the invention may be used as an inhibitorof urease activity (see, e.g., Tanaka et al., Bioorg Med Chem. 2004 Jan.15; 12(2):501-5).

In another embodiment, the compounds of the invention are useful fortreating or preventing Alzheimer's disease. Accordingly, the compoundsof the invention may be used as an inhibitor of amyloid-beta (Abeta)protein production, and accordingly as a potential treatment forAlzheimer's disease (see, e.g., Wallace et al., Bioorg Med Chem Lett.2003 Mar. 24; 13(6):1203-6).

In another embodiment, the compounds of the invention may be useful asanalgesics. For example, heterocyclic bicyclo[3.3.1]nonan-9-ones werefound to have a high affinity to kappa opioid receptors (see, e.g.,Brandt et al., Arch Pharm (Weinheim). 1996 June; 329(6):311-23). Inanother example, 2,4-di-2-pyridyl-substituted7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one-1,5-diester was found tohave a reasonable kappa-agonistic activity (see, e.g., Holzgrabe &Erciyas, Arch Pharm (Weinheim). 1992 October; 325(10):657-63).

In another embodiment, the compounds of the present invention may beuseful in preventing or treating cardiovascular diseases, such as, butnot limited to, hypertension, heart failure, pulmonary hypertension andrenal diseases. For example, bosentan, an endothelin receptorantagonist, has received approval by the Food and Drug Administration(FDA) for use in pulmonary artery hypertension (see, e.g., Vatter etal., Methods Find Exp Clin Pharmacol. 2004 May; 26(4):277-86). Thecompounds of the present invention, or a derivative thereof, may be usedas an endothelin receptor antagonist (see, e.g., Niiyama et al., BioorgMed Chem. 2002 November; 10(11):3437-44).

Due to their activity, the compounds of the invention are advantageouslyuseful in veterinary and human medicine.

When administered to a patient, a compound of the invention ispreferably administered as component of a composition that optionallycomprises a pharmaceutically acceptable vehicle the presentcompositions, which comprise a compound of the invention, are preferablyadministered orally. The compositions of the invention may also beadministered by any other convenient route, for example, by infusion orbolus injection, by absorption through epithelial or mucocutaneouslinings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.) and maybe administered together with another biologically active agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc., and can be used to administer the compounds of theinvention.

In certain embodiments, the present compositions may comprise one ormore compounds of the invention.

Methods of administration include but are not limited to intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes, or skin. The mode of administration is left to thediscretion of the practitioner. In most instances, administration willresult in the release of a compound of the invention into thebloodstream.

In specific embodiments, it maybe desirable to a compound of theinvention locally. This may be achieved, for example, and not by way oflimitation, by local infusion during surgery, topical application, e.g.,in conjunction with a wound dressing after surgery, by injection, bymeans of a catheter, by means of a suppository, or by means of animplant, said implant being of a porous, non-porous, or gelatinousmaterial, including membranes, such as sialastic membranes, or fibers.

In certain embodiments, it may be desirable to introduce a compound ofthe invention into the central nervous system by any suitable route,including intraventricular, intrathecal and epidural injection.Intraventricular injection may be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the compounds of the invention can be formulated asa suppository, with traditional binders and vehicles such astriglycerides.

In another embodiment, the compounds of the invention can be deliveredin a vesicle, in particular a liposome (see Langer, 1990. Science249:1527-1533; Treat et al, in Liposomes in the Therapy of InfectiousDisease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, N.Y., pp.353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid).

In yet another embodiment, the compounds of the invention can bedelivered in a controlled release system (see, e.g., Goodson, in MedicalApplications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).Other controlled-release systems discussed in the review by Langer,1990, Science 249:1527-1533) may be used. In one embodiment, a pump maybe used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.14:201; Buchwald et al., 1980, Surgery 88:507 Saudek et al., 1989, N.Engl. J. Med. 321:574). In another embodiment, polymeric materials canbe used (see Medical Applications of Controlled Release, Langer and Wise(eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled DrugBioavailability, Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, N.Y. (1984); Ranger and Peppas, 1983, J. Macromol. Sci.Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J.Neurosurg. 71:105). In yet another embodiment, a controlled-releasesystem can be placed in proximity of a target of a compound of theinvention, thus requiring only a fraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable vehicle so as to provide the form for properadministration to the patient.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, mammals, and more particularly inhumans. The term “vehicle” refers to a diluent, adjuvant, excipient, orcarrier with which a compound of the invention is administered. Suchpharmaceutical vehicles can be liquids, such as water and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical vehicles can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea, and the like. In addition,auxiliary, stabilizing, thickening. lubricating and coloring agents maybe used. When administered to a patient, the pharmaceutically acceptablevehicles are preferably sterile. Water is a preferred vehicle when thecompound of the invention is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid vehicles, particularly for injectable solutions.Suitable pharmaceutical vehicles also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The present compositions, if desired, can also contain minoramounts of wetting or emulsifying agents, or buffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical vehicles are described in Remington's PharmaceuticalSciences, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19thed., 1995, pp. 1447 to 1676, incorporated herein by reference.

In a preferred embodiment, the compounds of the invention are formulatedin accordance with routine procedures as a pharmaceutical compositionadapted for oral administration to human beings. Compositions for oraldelivery may be in the form of tablets, lozenges, aqueous or oilysuspensions, granules, powders, emulsions, capsules, syrups, or elixirs,for example. Orally administered compositions may contain one or moreagents, for example, sweetening agents such as fructose, aspartame orsaccharin; flavoring agents such as peppermint, oil of wintergreen, orcherry; coloring agents; and preserving agents, to provide apharmaceutically palatable preparation. Moreover, where in tablet orpill form, the compositions can be coated to delay disintegration andabsorption in the gastrointestinal tract thereby providing a sustainedaction over an extended period of time. Selectively permeable membranessurrounding an osmotically active driving compound are also suitable fororally administered compositions. In these later platforms, fluid fromthe environment surrounding the capsule is imbibed by the drivingcompound, which swells to displace the agent or agent compositionthrough an aperture. These delivery platforms can provide an essentiallyzero order delivery profile as opposed to the spiked profiles ofimmediate release formulations. A time delay material such as glycerolmonostearate or glycerol stearate may also be used. Oral compositionscan include standard vehicles such as mannitol, lactose, starch,magnesium stearate, sodium saccharine, cellulose, magnesium carbonate,etc. Such vehicles are preferably of pharmaceutical grade. Typically,compositions for intravenous administration comprise sterile isotonicaqueous buffer. Where necessary, the compositions may also include asolubilizing agent.

In another embodiment, the compounds of the invention can be formulatedfor intravenous administration. Compositions for intravenousadministration may optionally include a local anesthetic such aslignocaine to lessen pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a dry lyophilized powder or water freeconcentrate in a hermetically sealed container such as an ampoule orsachette indicating the quantity of active agent. Where the compounds ofthe invention are to be administered by infusion, they can be dispensed,for example, with an infusion bottle containing sterile pharmaceuticalgrade water or saline. Where the compounds of the invention areadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

The amount of a compound of the invention that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques. In addition, in vitro or in vivo assaysmay optionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on the route ofadministration, and the seriousness of the disease or disorder, andshould be decided according to the judgment of the practitioner and eachpatient's circumstances. However, suitable dosage ranges for oraladministration are generally about 0.001 milligram to about 200milligrams of a compound of the invention or a pharmaceuticallyacceptable salt thereof per kilogram body weight per day. In specificpreferred embodiments of the invention, the oral dose is about 0.01milligram to about 100 milligrams per kilogram body weight per day, morepreferably about 0.1 milligram to about 75 milligrams per kilogram bodyweight per day, more preferably about 0.5 milligram to 5 milligrams perkilogram body weight per day. The dosage amounts described herein referto total amounts administered; that is, if more than one compound of theinvention is administered, or if a compound of the invention isadministered with a therapeutic agent, then the preferred dosagescorrespond to the total amount administered. Oral compositionspreferably contain about 10% to about 95% active ingredient by weight.

Suitable dosage ranges for intravenous (i.v.) administration are about0.01 milligram to about 100 milligrams per kilogram body weight per day,about 0.1 milligram to about 35 milligrams per kilogram body weight perday, and about 1 milligram to about milligrams per kilogram body weightper day. Suitable dosage ranges for intranasal administration aregenerally about 0.01 pg/kg body weight per day to about 1 mg/kg bodyweight per day. Suppositories generally contain about 0.01 milligram toabout 50 milligrams of a compound of the invention per kilogram bodyweight per day and comprise active ingredient in the range of about 0.5%to about 10% by weight.

Recommended dosages for intradermal, intramuscular, intraperitoneal,subcutaneous, epidural, sublingual, intracerebral, intravaginal,transdermal administration or administration by inhalation are in therange of about 0.001 milligram to about 200 milligrams per kilogram ofbody weight per day. Suitable doses for topical administration are inthe range of about 0.001 milligram to about 1 milligram, depending onthe area of administration. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.Such animal models and systems are well known in the art.

The invention also provides pharmaceutical packs or kits comprising oneor more vessels containing one or more compounds of the invention.Optionally associated with such container(s) can be a notice in the formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of manufacture, use or sale for humanadministration. In a certain embodiment, the kit contains more than onecompound of the invention. In another embodiment, the kit comprises atherapeutic agent and a compound of the invention.

The compounds of the invention are preferably assayed in vitro and invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. For example, in vitro assays can be used to determine whetherit is preferable to administer a compound of the invention alone or incombination with another compound of the invention and/or a therapeuticagent. Animal model systems can be used to demonstrate safety andefficacy.

Other methods will be known to the skilled artisan and are within thescope of the invention.

In certain embodiments of the present invention, a compound of theinvention can be used in combination therapy with at least one othertherapeutic agent. The compound of the invention and the therapeuticagent can act additively or, more preferably, synergistically. In apreferred embodiment, a composition comprising a compound of theinvention is administered concurrently with the administration ofanother therapeutic agent, which can be part of the same composition asor in a different composition from that comprising the compound of theinvention. In another embodiment, a composition comprising a compound ofthe invention is administered prior or subsequent to administration ofanother therapeutic agent. As many of the disorders for which thecompounds of the invention are useful in treating are chronic, in oneembodiment combination therapy involves alternating betweenadministering a composition comprising a compound of the invention and acomposition comprising another therapeutic agent, e.g., to minimize thetoxicity associated with a particular drug. The duration ofadministration of the compound of the invention or therapeutic agent canbe, e.g., one month, three months, six months, a year, or for moreextended periods. In certain embodiments, when a compound of theinvention is administered concurrently with another therapeutic agentthat potentially produces adverse side effects including, but notlimited to, toxicity, the therapeutic agent can advantageously beadministered at a dose that falls below the threshold at which theadverse side is elicited.

The therapeutic agent can be an anti-cancer agent. Useful anti-canceragents include, but are not limited to, methotrexate, taxol,mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide,ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin,dacarbazine, procarbizine, etoposides, campathecins, bleomycin,doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin,mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine,paclitaxel, and docetaxel, .gamma.-radiation, alkylating agentsincluding nitrogen mustard such as cyclophosphamide, Ifosfamide,trofosfamide, Chlorambucil, nitrosoureas such as carmustine (BCNU), andLomustine (CCNU), alkylsulphonates such as busulfan, and Treosulfan,triazenes such as Dacarbazine, platinum containing compounds such asCisplatin and carboplatin, plant alkaloids including vinca alkaloids,vincristine, Vinblastine, Vindesine, and Vinorelbine, taxoids includingpaclitaxel, and Docetaxol, DNA topoisomerase inhibitors includingEpipodophyllins such as etoposide, Teniposide, Topotecan,9-aminocamptothecin, campto irinotecan, and crisnatol, mytomycins suchas mytomycin C, and Mytomycin C, anti-metabolites, includinganti-folates such as DHFR inhibitors, methotrexate and Trimetrexate, IMPdehydrogenase inhibitors including mycophenolic acid, Tiazofurin,Ribavirin, EICAR, Ribonucleotide reductase Inhibitors such ashydroxyurea, deferoxamine, pyrimidine analogs including uracil analogs5-Fluorouracil, Floxuridine, Doxifluridine, and Ratitrexed, cytosineanalogs such as cytarabine (ara C), cytosine arabinoside, andfludarabine, purine analogs such as mercaptopurine, thioguanine,hormonal therapies including receptor antagonists, the anti-estrogensTamoxifen, Raloxifene and megestrol, LHRH agonists such as goscrclin,and Leuprolide acetate, anti-androgens such as flutamide, andbicalutamide, retinoids/deltoids, Vitamin D3 analogs including EB 1089,CB 1093, and KH 1060, photodyamic therapies including vertoporfin(BPD-MA), Phthalocyanine, photosensitizer Pc4, Demethoxy-hypocrellin A,(2BA-2-DMHA), cytokines including Interferon-.alpha.,Interferon-.gamma., tumor necrosis factor, as well as other compoundshaving anti-tumor activity including Isoprenylation inhibitors such asLovastatin, Dopaminergic neurotoxins such as 1-methyl-4-phenylpyridiniumion, Cell cycle inhibitors such as staurosporine, Actinomycins such asActinomycin D and Dactinomycin, Bleomycins such as bleomycin A2,Bleomycin B2, and Peplomycin, anthracyclines such as daunorubicin,Doxorubicin (adriamycin), Idarubicin, Epirubicin, Pirarubicin,Zorubicin, and Mitoxantrone, MDR inhibitors including verapamil, andCa²⁺ ATPase inhibitors such as thapsigargin.

The therapeutic agent can be an antiviral agent. Useful antiviral agentsinclude, but are not limited to, nucleoside analogs, such as zidovudine,acyclovir, gangcyclovir, vidarabine, idoxuridine, trifluridine, andribavirin, as well as foscarnet, amantadine, rimantadine, saquinavir,indinavir, ritonavir, and the alpha-interferons.

The therapeutic agent can be an anti-inflammatory agent. Usefulanti-inflammatory agents include, but are not limited to, non-steroidalanti-inflammatory drugs such as salicylic acid, acetylsalicylic acid,methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine,acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, diclofenac, ibuprofen,naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine,aminopyrine, apazone and nimesulide; leukotriene antagonists including,but not limited to, zileuton, aurothioglucose, gold sodium thiomalateand auranofin; and other anti-inflammatory agents including, but notlimited to, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone.

The invention will now be further described by way of the followingnon-limiting examples.

EXAMPLES

The catalyst of formula (IV) can be synthesized using previously knownmethods in the art. The heterocyclic compound could be synthesized fromnatural or synthesized proline. The tetrazole derivative shown informula (IVb) could be synthesized by a reported method (TetrahedronLett., vol. 36, 7115-7118, (1995); and J. Med. Chem., vol. 28,1067-1071, (1985)). Thus, commercially availableN-(benzyloxycarbonyl)-L-proline is converted to an amide via a reactionwith ammonia and dehydrated with phosphorousoxychloride to give nitrile.The obtained nitrile is treated with sodium azide to give a tetrazoleand the Cbz (benzyloxycarbonyl) group is deprotected with HBr/AcOH orPd/C, H₂ to give the tetrazole derivative which is shown in formula(IVa). An example of this preparative scheme is described in detailbelow:

Preparation of L-Pyrrolidine-2-yl-1H-tetrazole (catalyst of formula(IVa)) Preparation of N-benzyloxycarbonyl-L-prolinamide

The ammonium hydrogencarbonate (1.26 equiv) was added to the stirredsolution of carbobenzyloxy-L-proline (1 equiv), pyridine and Boc₂O (1.30equiv) in acetonitrile and stirred for 20 h. The solvent was removed,and the residue was diluted with ethyl acetate, washed with water,extracted with ethyl acetate, dried over MgSO₄ and evaporated in vacuoto afford N-benzyloxycarbonyl-L-prolinamide as colorless crystals. ¹HNMR (CDCl₃, 400 MHz) δ7.36 (m, 5H, Ar—H), 6.71 (s, 1H, NHH), 5.81 (s,1H, NHH), 5.20 (d, 1H, J=12 Hz, OCHH), 5.15 (d, 1H, J=12 Hz, OCHH), 4.32(m, 1H, NCH), 3.53 (m, 2H, NCH₂), 1.91-2.33 (m, 4H, CH₂CH₂);

Preparation of N-benzyloxycarbonyl-L-proline nitrile

The phosphorus oxychloride in dichloromethane was added over 10 min tothe solution of N-benzyloxycarbonyl-L-prolinamide in dry pyridine at−5˜−10° C. under N₂. The mixture was stirred at −5˜−10° C. for 1 h andthen it was poured on ice and extracted with saturated cupric sulfatesolution and saturated sodium chloride solution, dried over MgSO₄ andevaporated to in vacuo to afford N-benzyloxycarbonyl-L-proline nitrileas a pale yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ7.96 (d, 2H, J=7.2 Hz,Ar—H), 7.90 (t, 1H, J=7.2 Hz, Ar—H), 7.77 (t, 2H, J=8.0 Hz, Ar—H), 4.80(t, 1H), 3.28-3.36 (m, 2H), 2.34-2.52 (m, 1H), 2.04-2.20 (m, 3H);

Preparation of N-benzyloxycarbonyl pyrroridine-L-2-yl-1H-tetrazole

The mixture of N-benzyloxycarbonyl-L-prolinamide (1 equiv), sodium azide(1.04 equiv), ammonium chloride (1.1 equiv), and dry DMF was stirred at90˜95° C. under N₂ for 6 h. The mixture was poured onto ice, acidifiedto pH 2 with diluted HCl, and extracted with CHCl₃. The CHCl₃ layer waswashed with water and saturated sodium chloride, dried over Na₂SO₄, andevaporated in vacuo to afford crude material. This crude material waspurified with silicagel chromatography to pure N-benzyloxycarbonylpyrroridine-L-2-yl-1H-tetrazole. ¹H NMR (CDCl₃, 400 MHz) δ7.37 (s, 5H),5.20 (m, 3H), 3.55 (m, 2H), 2.06-2.34 (m, 4H).

Preparation of L-pyrrolidine-2-yl-1H-tetrazole

N-benzyloxycarbonyl pyrrolidine-L-2-yl-1H-tetrazole, and 10% palladiumon charcoal in acetic acid/water (9:1) was stirred under H₂ at roomtemperature for 4 h. The mixture was filtered through Celite and thefiltrate was evaporated in vacuo to afford crudeL-pyrrolidine-2-yl-1H-tetrazole, which was recrystallized from aceticacid and diethyl ether. [α]_(D) ²⁵+14.1° (c=0.12, MeOH); ¹H NMR (CD₃OD,400 MHz) δ4.82 (m, 2H), 3.33 (m, 2H), 2.39 (m, 1H), 2.02-2.41 (m, 3H);¹³C NMR (CD₃OD, 100 MHz) δ159.6, 56.2, 46.6, 31.1, 24.8.

The tetrazole derivative of formula (IVb) could also be prepared byfollowing the reported method from Organic Letters, 2001, Vol. 3, No.25, 4091-4094; Organic Letters, 2002, Vol. 4 No. 15, 2525-2527).

Example 1 General Procedure for the Enantioselective O-Nitroso AldolReaction Between a Ketone and Nitrosobenzene in the Presence of(L)-Pyrrolidine-Based Tetrazole Catalyst of Formula IVb

To a room temperature solution of pyrrolidine-based tetrazole catalyst(5 mol %) and ketone (1.5 mmol, 3 eq) in DMSO (1 ml) was added thesolution of nitrosobenzene (0.5 mmol, 1 eq) in DMSO (1 mL) dropwise for1 h. The resulting mixture was stirred at this temperature until thenitrosobenzene was completely consumed (1 h), as determined by TLC(hexane/ethyl acetate=3/1). The reaction mixture was then poured into aniced saturated NH₄Cl solution. The aqueous layer was extracted withethyl acetate (20 mL×3). The combined organic extracts were washed withbrine, dried over Na₂SO₄ with cooling and concentrated under reducedpressure after filtration. The residual crude product waschromatographed on a two-layered column filled with Florisil® (upperlayer) and silica gel (lower layer) using a mixture of ethyl acetate andhexane as the eluant to give the product.

Example 2 General Procedure for the Enantioselective O-Nitroso AldolReaction Between an Aldehyde and Nitrosobenzene in the Presence of(L)-Pyrrolidine-Based Tetrazole Catalyst of Formula IVb

To a room temperature solution of pyrrolidine-based tetrazole catalyst(10 mol %) in acetonitrile (1 mL) was added nitrosobenzene (1 equiv, 0.5mmol) in one portion and stirred at room temperature for 10 min. To thisgreen heterogeneous solution was then added aldehyde (3 equiv, 1.5 mmol)in one portion. The resulting mixture was stirred at this temperatureuntil the nitrosobenzene was completely consumed (15˜30 min), asdetermined by TLC (hexane/ethyl acetate=2/1). Then, the reaction wastransferred to a methanol suspension of NaBH₄ at 0° C. After 20 min, thereaction mixture was then poured into saturated NH₄Cl solution. Theaqueous layer was extracted with diethyl ether (20 mL×3). The combinedorganic extracts were dried over Na₂SO₄ with cooling and concentratedunder reduced pressure after filtration. The residual crude product waschromatographed on column filled with silica gel using a mixture ofethyl acetate and hexane as the eluant to give the product.

Example 3 Procedure for the Synthesis of α-Hydroxy Cyclohexanone

To a room temperature solution of pyrrolidine-based tetrazole catalyst(5 mol %) and cyclohexanone (3 equiv, 1.5 mmol) in DMSO (1 mL) was addedthe solution of nitrosobenzene (1 equiv, 0.5 mmol) in DMSO (1 mL)dropwise for 1 h. The resulting mixture was stirred at this temperatureuntil the nitrosobenzene was completely consumed (1 h), as determined byTLC (hexane/ethyl acetate=3/1). After cooling to 0° C., CuSO₄ (0.3 eq)and MeOH (3 mL) were added and stirred at 0° C. for 10 h. The reactionmixture was quenched by cooled brine (20 mL) and the aqueous layer wasextracted with ethyl acetate (10 mL×3). The combined organic extractswere washed with brine, dried over Na₂SO₄ with cooling and concentratedunder reduced pressure after filtration. The residual crude product waschromatographed on a silica gel using a mixture of ethyl acetate andhexane as the eluant to give the product.

Example 4 Procedure for the Synthesis of 1,2-Cyclohexanediol

The solution of α-hydroxy cyclohexanone formed in Example 3 (1 equiv,0.8 mmol) in MeOH (1 mL) was added to a methanol suspension of NaBH₄ at0° C. and stirred at this temperature for 1 h. Then, the reactionmixture was poured into a saturated NH₄Cl solution. The aqueous layerwas extracted with diethyl ether (20 mL×3). The combined organicextracts were dried over Na₂SO₄ with cooling and concentrated underreduced pressure after filtration. The residual crude product waschromatographed on a column filled with silica gel using a mixture ofethyl acetate and hexane as the eluant to give the product.

Example 5 Specific Examples of the Enantioselective O-Nitroso AldolReaction Between Ketone or Aldehyde and Nitrosobenzene in the Presenceof (L)-Pyrrolidine-Based Tetrazole Catalyst of Formula IVb

The enantioselective O-nitroso aldol between various ketones oraldehydes and nitrosobenzene was investigated (see FIG. 3). The resultsof these reactions are displayed in Table 1. For reactions with cyclicketones (examples 5a-5d), optimal results were obtained with 5 mol % of(L)-pyrrolidine-tetrazole catalyst IVb. As shown in Table 1, thereactions between cyclic ketones and nitrosobenzene proceeded cleanly toafford O-adducts IIa in 87-97% yield and with >99% ee. Production of thecorresponding N-adducts IIb was negligibe in all cases.

With acyclic ketones (Example 5e) and aldehydes (Examples 5f-5h), theenantioselectivities were still maintained in excellent levels, butyields of O-nitroso aldol products (Ia) were moderate owing in part tothe production of the N-adducts. Yields of the desired α-aminooxyketonesor α-aminooxyaldehydes could be increased by increasing the amount ofcatalyst. For example, with 10-20 mol % catalyst, reactions betweenaldehydes in examples 5f-5h of Table 1 and nitrosobenzene under standardconditions (see footnotes in Table 1) gave 67-75% yield of the desiredα-aminooxyaldehydes and a negligible amount of the correspondingN-adduct. Reaction between methyl ethyl ketone (example 5e) andnitrosobenzene in the presence of 20 mol % of the catalyst gave 54% ofthe desired O-adduct and 21% of the N-adduct.

TABLE 1 Examples of enantioselective O-nitroso aldol reactions betweenvarious ketones or aldehydes and nitrosobenzene catalyzed by compoundIVb.* yield, ee, % Entry Reagent Example*** %^(¶) (product)^(††)(configuration)^(§§) 1**

5a  94  >99 (S) 2**

5b  87  >99 (S) 3**

5c  97   99 (S) 4**

5d  95  >99 (S) 5^(†)

5e  54  >99 (S) 6‡

5f^(∥) 67^(∥)  98 (R) 7^(§)

5g^(∥) 65^(∥)  98 (R) 8^(‡)

5h^(∥) 69^(∥)  98 (R) *All reactions were conducted with 1.0 equiv ofnitrosobenzene, 3 equiv of ketone (or aldehyde), specified mol % ofcatalyst IVa, and specified solvent at room temperature. **Performedwith 5 mol % of IVb in DMSO. ^(†)Performed with 20 mol % of IVb in DMSO.^(‡)Performed with 10 mol % of IVb in MeCN. ^(§)Performed with 20 mol %of IVb in MeCN. ***Purifucation procedures, physical data, andspectroscopic data for each individual example are provided below.^(¶)Isolated yield - Determined by yield of corresponding primaryalcohol obtained after reduction of product. ^(††)Determined by chiralHPLC (for separation conditions, refer to examples below).^(§§)Determined after conversion to the corresponding diol (See Example7 below).

The methods of purifying the products in Table 1 are discussed below.Also provided are the physical and spectroscopic data of the isolatedproducts along with the chiral columns and experimental conditions usedto separate the enantiomers of the isolated products. Note thatα-aminooxyaldehydes were converted to corresponding primary alcohols todetermine yield.

Example 5a 2-(N-Phenyl aminooxy)cyclohexanone

Purification by flash column chromatography with elution by hexane:ethylacetate (10:1) provided as a yellowish powder. TLC R_(f)=0.30 (3:1hexane:ethyl acetate); [α]_(D) ²⁷+122.0° (c=2.83, CHCl₃); IR (CHCl₃)3021, 2951, 2872, 1722, 1603, 1495, 1132, 1100, 1073, 1028, 928 cm⁻¹; ¹HNMR (CDCl₃, 300 MHz) δ7.82 (s, 1H, NH), 7.25 (t, 2H, J=8.4 Hz, Ar—H),6.94 (t, 3H, J=8.1 Hz, Ar—H), 4.35 (q, 1H, J=6.0 Hz, CH), 2.34-2.48 (m,2H, CH₂), 2.00-2.02 (m, 2H, CH₂), 1.71-1.79 (m, 4H, CH₂); ¹³C NMR(CDCl₃, 75 MHz) δ209.9, 148.0, 128.8 (2C), 122.0, 114.3 (2C), 86.2,40.8, 32.5, 27.2, 23.7; Anal. Calcd for C₁₂H₁₅NO₂: C, 70.22; H, 7.37; N,6.82. Found: C, 70.22; H, 7.42; N, 6.91. Enantiomeric excess wasdetermined by HPLC with a Chiralcel AD column (40:1 hexane:2-propanol),1.0 mL/min; major enantiomer t_(r)=34.3 min, minor enantiomer t_(r)=28.1min.

Example 5b 2-(N-Phenyl aminooxy)tetrahydro-4H-pyran-4-one

Purification by flash column chromatography with elution by hexane:ethylacetate (5:1) provided as a yellowish powder. TLC R_(f)=0.079 (5:1hexane:ethyl acetate); [α]_(D) ²⁷+63.0° (c=0.2, CHCl₃); IR (CHCl₃) 3262,2990, 2886, 1708, 1659, 1587, 1478, 1273, 1125, 1081, 988, 968, 860cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ7.77 (s, 1H, NH), 7.26 (t, 2H, J=7.8 Hz,Ar—H), 6.97 (t, 1H, J=7.4 Hz, Ar—H), 6.92 (d, 2H, J=7.8 Hz, Ar—H),4.48-4.52 (m, 1H, CH₂), 4.40-4.45 (m, 1H, CH₂) 4.16-4.19 (m, 1H, CH),3.66-3.74 (m, 2H, CH₂), 2.66-2.71 (m, 1H, CH₂), 2.57 (td, 1H, J=2.9,14.3 CH₂); ¹³C NMR (CDCl₃, 100 MHz) δ205.4, 147.7, 128.9 (2C), 122.5,114.7 (2C), 83.5, 70.0, 68.1, 42.3; MS (CI) Exact Mass Calcd forC₁₁H₁₃NO₃ (M+H)⁺: 208.1. Found: 208.1. Enantiomeric excess wasdetermined by HPLC with a Chiralcel AD-H column (9:1 hexane:2-propanol),1.0 mL/min; major enantiomer t_(r)=19.8 min, minor enantiomer t_(r)=26.5min.

Example 5c 7-(N-Phenyl aminooxy) 1,4-dioxa-spiro[4.5]decan-8-one

Purification by flash column chromatography with elution by hexane:ethylacetate (7:1) provided as a yellowish powder. TLC R_(f)=0.18 (3:1hexane:ethyl acetate); [α]_(D) ²⁷+40.6° (c=2.3, CHCl₃); IR (CHCl₃) 3164,2989, 1855, 1764, 1580, 1382, 861 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ7.84(s, 1H, NH), 7.24 (t, 2H, J=7.5 Hz, Ar—H), 6.92 (t, 3H, J=8.1 Hz, Ar—H),4.64 (q, 1H, J=5.7 Hz, CH), 4.05 (s, 4H, CH₂), 2.65-2.81 (m, 1H, CH₂),2.42-2.50 (m, 4H, CH₂), 1.99-2.05 (m, 1H, CH₂); ¹³C NMR (CDCl₃, 100 MHz)δ210.3, 147.9, 128.8 (2C), 122.0, 114.3 (2C), 107.5, 82.6, 64.6, 64.5,39.6, 35.9, 34.3; MS (CI) Exact Mass Calcd for C₁₄H₁₇NO₄ (M+H)⁺: 264.0.Found: 264.10. Enantiomeric excess was determined by HPLC with aChiralcel OD-H column (9:1 hexane:2-propanol), 0.5 mL/min; majorenantiomer t_(r)=20.2 min, minor enantiomer t_(r)=23.2 min.

Example 5d 1-Phenylacethyl-3-(N-phenyl aminooxy)piperidin-4-one

(5d, entry 4, Table 2). Purification by flash column chromatography withelution by hexane:ethyl acetate (3:1) provided as a yellowish oil. TLCR_(f)=0.10 (2:1 hexane:ethyl acetate); [α]_(D) ³⁰+25.7° (c=0.7, CHCl₃);IR (neat) 3269, 3033, 2954, 1710, 1649, 1547, 1480, 1411, 1365, 1277,1110, 986, 910 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ7.75 (bs, 1H, NH),7.25-7.37 (m, 8H, Ar—H), 7.22 (t, 2H, J=7.5 Hz, Ar—H), 6.94 (t, 2H,J=7.4 Hz, Ar—H), 4.36 (b, 1H, CH), 3.75 (t, 2H, CH₂), 3.55 (q, 1H, CH₂),3.37-3.44 (m, 1H, CH₂), 2.55 (b, 2H, CH₂), 2.41 (b, 2H, CH₂); ¹³C NMR(CDCl₃, 100 MHz) δ205.4, 155.1, 136.4, 128.8 (3C), 128.4, 128.2, 127.9(2C), 122.3, 114.5 (2C), 82.9, 67.9, 64.5, 47.0, 43.7, 42.9, 40.8; MS(CI) Exact Mass Calcd for C₁₉H₂₀N₂O₃ (M−H)⁺: 323.1. Found: 323.1.Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column(9:1 hexane:2-propanol), 1.0 mL/min; major enantiomer t_(r)=36.5 min,minor enantiomer t_(r)=26.0 min.

Example 5e 3-(N-phenyl aminooxy) butan-2-one

Purification by flash column chromatography with elution by hexane:ethylacetate (10:1) provided as a yellowish oil. TLC R_(f)=0.20 (5:1hexane:ethyl acetate); [α]_(D) ²⁵+57.4° (c=3.8, CHCl₃); IR (neat) 3572,1815, 1765, 1711, 1582, 1484, 1382, 837, 780 cm⁻¹; ¹H NMR (CDCl₃, 400MHz) δ7.37 (s, 1H, NH), 7.26 (t, 2H, J=7.4 Hz, Ar—H), 6.96 (t, 3H, J=8.5Hz, Ar—H), 4.43 (q, 1H, CH), 2.20 (s, 3H, CH₃), 1.42 (d, 3H, J=7.0 Hz,CH₃); ¹³C NMR (CDCl₃, 100 MHz) δ209.6, 148.2, 129.3 (2C), 122.7, 114.8(2C), 84.8, 25.9, 15.8; MS (EI) Exact Mass Calcd for C₁₀H₁₃NO₂ (M): 179.Found: 179. Enantiomeric excess was determined by HPLC with a ChiralcelAD-H column (40:1 hexane:2-propanol), 0.5 mL/min; major enantiomert_(r)=45.2 min, minor enantiomer t_(r)=47.6 min.

3-(N-phenyl hydroxyamino)butan-2-one

Purification by flash column chromatography with elution by hexane:ethylacetate (10:1) provided as yellowish oil. TLC R_(f)=0.15 (5:1hexane:ethyl acetate); [α]_(D) ²⁵−6.3° (c=0.12, CHCl₃); IR (neat) 3623,3141, 1855, 1659, 1580, 1468, 1291, 1161, 852 cm⁻¹; ¹H NMR (CDCl₃, 400MHz) δ7.32 (t, 2H, J=7.4 Hz, Ar—H), 7.10 (d, 2H, J=7.7 Hz, Ar—H), 6.97(t, 1H, J=7.6 Hz, Ar—H), 5.80 (s, 1H, N—OH), 4.24 (q, 1H, J=7.6 Hz, CH),2.26 (s, 3H, CH₃), 1.31 (d, 3H, J=6.7 Hz, CH₃); ¹³C NMR (CDCl₃, 100 MHz)δ209.4, 150.7, 129.3 (2C), 122.3, 116.5 (2C), 69.98, 27.4, 10.8; MS (EI)Exact Mass Calcd for C₁₀H₁₃NO₂ (M): 179. Found: 179. Enantiomeric excesswas determined by HPLC with a Chiralcel AD-H column (40:1hexane:2-propanol), 0.5 mL/min; major enantiomer t_(r)=28.9 min, minorenantiomer t_(r)=25.9 min.

Example 5f 3-Phenyl-2-(N-phenyl aminooxy)-propan-1-ol

Purification by flash column chromatography with elution by hexane:ethylacetate (6:1) provided as yellowish oil. TLC R_(f)=0.27 (2:1hexane:ethyl acetate); [α]_(D) ²⁰+26.0 (c=1.07, CHCl₃); IR (neat) 3314,2976, 2862, 1599, 1491, 1452, 1402, 1250, 1105, 1039, 910.5; ¹Hδ7.40-7.12 (m, 8H), 6.94 (t, J=7.2 Hz, 1H), 6.82 (dd, J=0.9, 8.7 Hz,1H), 4.13 (dddd, J=2.7, 6.9, 6.3, 6.3 Hz, 1H), 3.85 (dd, J=2.7, 12 Hz,1H), 3.71 (dd, J=5.7, 12 Hz, 1H), 3.04 (dd, J=6.9, 13.8 Hz, 1H), 2.84(dd, J=6.9, 13.8 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ148.2, 137.7, 129.4,128.9, 128.4, 126.4, 122.3, 114.5, 84.9, 64.1, 36.3; HRMS exact masscalcd for (C₁₂H₁₇NO₂) requires m/z 243.1259, found m/z 243.1251.Enantiomeric excess was determined by HPLC with a Chiralcel AD column(95:5 hexane:ethanol), 1.0 mL/min; major enantiomer t_(r)=42.8 min,minor enantiomer t_(r)=40.1 min.

Example 5g 3-Methyl-2-(N-phenyl aminooxy)-butan-1-ol

Purification by flash column chromatography with elution by hexane:ethylacetate (4:1) provided as a yellowish oil. TLC R_(f)=0.22 (2:1hexane:ethyl acetate); [α]_(D) ²⁰+18.3 (c=1.03, CHCl₃); IR (neat) 3400,3269, 3047, 2963, 2878, 1599, 1491, 1468, 1412, 1238, 1051, 1024, 978.0,908.6, 771.6, 735.0, 694.5 cm⁻¹; ¹H NMR (300 MHz) δ7.38-7.20 (m, 3H),7.10-6.95 (m, 3H), 3.92-3.85 (m, 2H), 3.80-3.70 (m, 1H), 2.65 (t, J=5.7Hz, 1H), 2.12-1.95 (m, 1H), 1.05 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz,3H); ¹³C NMR (75 MHz, CDCl₃) δ148.2, 128.9, 122.3, 114.8, 88.5, 63.4,28.6, 18.7, 18.5; HRMS exact mass calcd for (C₁₁H₁₇NO₂) requires m/z195.1259, found m/z 195.1239. Enantiomeric excess was determined by HPLCwith a Chiralcel AD column (95:5 hexane:ethanol), 1.0 mL/min; majorenantiomer t_(r)=16.2 min, minor enantiomer t_(r)=14.8 min.

Example 5h 2-(N-Phenyl aminooxy)-hexan-1-ol

Purification by flash column chromatography with elution by hexane:ethylacetate (6:1) provided as a yellowish oil. TLC R_(f)=0.36 (2:1hexane:ethyl acetate); [α]_(D) ²⁰+14.1 (c=1.08, CHCl₃); IR (neat) 3377,3144, 2955, 1601, 1493, 1464, 1377, 1240, 1030, 902.8, 769.7; ¹H NMR(300 MHz, CDCl₃) δ7.34-7.20 (m, 2H), 7.04-6.94 (m, 3H), 3.96 (dddd,J=2.4, 6.6, 6.6, 6.6 Hz, 1H), 3.91-3.72 (m, 2H), 2.48 (m, 1H), 1.80-1.20(m, 7H), 0.92 (t, J=6.6 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ148.3, 128.8,122.1, 114.5, 83.8, 64.9, 29.5, 27.8, 22.7, 13.8; HRMS exact mass calcdfor (C₁₂H₁₉NO₂) requires m/z 209.1416, found m/z 209.1401. Enantiomericexcess was determined by HPLC with a Chiralcel AD column (95:5hexane:ethanol), 1.0 mL/min; major enantiomer t_(r)=19.5 min, minorenantiomer t_(r)=17.9 min.

Example 6 Comparison of Different (L)-Pyrrolidine Catalysts in theEnantioselective O-Nitroso Aldol Reaction Between Cyclohexanone andNitrosobenzene

With the O-nitroso aldol reaction between cyclohexanone andnitrosobenzene as a model reaction, several different (L)-pyrrolidonecatalysts were assessed. The general reaction scheme and the differentcatalysts employed are displayed in FIG. 4. The results with variouscatalysts are summarized in Table 2. Notably, several kinds ofsubstituted pyrrolidine catalysts (IVc-IVe) were unable to catalyze thenitroso aldol process after I day at room temperature. Thediamine-protonic acid catalyst (IVf) afforded O-adduct with Rconfiguration, but did not provide catalyst turnover. (L)-proline (IVg)and pyrrolidine-based tetrazole (IVb) afforded promising level ofregioselection and enantioselection with S configuration for theO-nitroso aldol adduct. Catalyst IVb was particularly attractive interms of higher reactivity.

The difference of reactivity in O-nitroso Aldol reactions catalyzed byequal amounts different proline compounds was demonstrated by addingboth (D)-proline and catalyst IVb (L-configuration) to the reactionbetween cyclohexanone and nitrosobenzene. The two catalysts wouldgenerate the same product, albeit with different handedness. Thereaction scheme is shown in FIG. 5. Clearly, the (S)-enantiomer is thedominant product. Hence, compound IVb catalyzes the O-nitroso Aldolreaction at a rate faster than the same reaction catalyzed by prolineitself.

TABLE 2 Catalyst survey of O-nitroso aldol reaction.* catalyst yield, eeof a, entry (mol %) time %^(†) a/b/c %^(§) (conf.)^(¶) 1 IVc (5) 1 day<1 2 IVd (5) 1 day <1 3 IVe (5) 1 day <1 4 IVf (5) 1 h 4 >99/—/— 37 (R)5 IVg (5) 1 h 35   98/—/2− >99 (S) 6 IVb (5) 1 h 94 >99/—/— >99 (S) 7IVb (3) 1 h 72 >99/—/— >99 (S) 8 IVb (2) 1 h 50 >99/—/— >99 (S)*Reactions were conducted with catalytic amount of IV, 1.0 equiv ofnitrosobenzene, and 3 equiv of cyclohexanone in DMSO at roomtemperature. ^(†)Isolated yield. ^(§)Determined by HPLC, CHIRALPAK AD.^(¶)Determined after conversion to the corresponding diol (see Example 7below).

Example 7 Determination of the Absolute Configuration ofα-Hydroxyketones

The absolute configuration of α-aminooxy compounds were determined byreduction to the corresponding diols. FIG. 6A shows an example ofconversion of a ketone into a 1,2-diol. First, the ketone is convertedinto an enantioenriched α-aminooxyketone through an enantioselectiveO-nitroso aldol reaction. Reactions with CuSO₄ afford the correspondingα-hydroxyketone product. Reduction of the α-hydroxyketone with NaBH₄gives the diol product. FIG. 6B shows an example of conversion ofaldehyde into a 1,2-diol. Here, the sequence of reduction with CuSO₄ andNaBH₄ is reversed relative to the reaction with ketone.

Examples of the α-aminooxyaldehydes which can be obtained by thisinvention include but are not limited to:

-   (N-isobutylaminooxy)acetaldehyde,-   [N-(1,1-dimethylbutyl)]aminooxyacetaldehyde,-   (N-phenylaminooxy)acetaldehyde,-   2-(N-isobutylaminooxy)propanal,-   2-[N-(1,1-dimethylbutyl)aminooxy]propanal,-   2-N-phenylaminooxypropanal,-   2-(N-isobutylaminooxy)butanal,-   2-[N-(1,1-dimethylbuthyl)aminooxy]-2-methylpropanal,-   2-(N-phenylaminooxy)2-methylpropanal,-   2-(N-isobutylaminooxy)-4-methylbutanal,-   2-[N-(1,1-dimethylbutyl)aminooxy-4-methylbutanal,-   2-(N-phenylaminooxy)-4-methylbutanal 2-(N-isobutylaminooxy)hexanal,-   2-[N-(1,1-dimethylbutyl)aminooxyhexanal,-   2-(N-phenylaminooxy)hexanal, 2-(N-isobutylaminooxy)heptanal,-   2-[N-(1,1-dimethylbutyl)aminooxyheptanal,-   2-(N-phenylaminooxy)heptanal,-   2-(N-isobutylaminooxy)octanal,-   2-[N-(1,1-dimethylbutyl)aminooxyoctanal,-   2-(N-phenylaminooxy)octanal,-   2-(N-isobutylaminooxy)nonanal,-   2-[N-(1,1-dimethylbutyl)aminooxynonanal,-   2-(N-phenylaminooxy)nonanal,-   2-(N-isobutylaminooxy)decanal,-   2-[N-(1,1-dimethylbutyl)aminooxydecanal,-   2-(N-phenylaminooxy)decanal,-   2-(N-isobutylaminooxy)undecanal,-   2-[N-(1,1-dimethylbutyl)aminooxyundecanal,-   2-(N-phenylaminooxy)undecanal,-   2-(N-isobutylaminooxy)dodecanal,-   2-[N-(1,1-dimethylbutyl)aminooxydodecanal,-   2-(N-phenylaminooxy)dodecanal,-   2-(N-isobutylaminooxy)tridecanal,-   2-[N-(1,1-dimethylbutyl)aminooxytridecanal; and-   2-(N-phenylaminooxy)tridecanal.

Examples of compounds which can be obtained as α-aminooxyaldehydesinclude but are not limited to:

-   2,3-bis(N-isobutylaminooxy)butanedial,-   2,3-bis[N-1,1-dimethylbutyl]aminooxy]butanedial,-   2,3-bis[N-phenylaminooxy]butanedial,-   2-N-isobutylaminooxy-2-propenal,-   2-N-(1,1-dimethylbutyl)aminooxy-2-propenal,-   2-N-phenylaminooxy-2-propenal,-   2-N-isobutylaminooxy-2-butenal,-   2-N-(1,1-dimethylbutyl)aminooxy-2-butenal,-   2-N-phenylaminooxy-2-butenal,-   3-phenyl-2-N-isobutylaminooxy-2-propenal,-   3-phenyl-2-N-(1,1-dimethylbutyl)aminooxy-2-propenal; and-   3-phenyl-2-N-phenylaminooxy-2-propenal.

Examples of the α-aminooxyketones which can be obtained by thisinvention include but are not limited to:

-   (N-isobutylaminooxy)acetone,-   [N-(1,1-dimethylbutyl)aminooxy]acetone,-   (N-phenylaminooxy)acetone,-   3-(N-isobutylaminooxy)butane-2-one,-   3-[N-(1,1dimethylbutyl)aminooxy]butane-2-one,-   (N-phenylaminooxy)butane-2-one,-   3-(N-isobutylaminooxy)pentane-2-one,-   3-[N-(1,1dimethylbutyl)aminooxy]pentane-2-one,-   (N-phenylaminooxy)pentane-2-one,-   3-(N-isobutylaminooxy)-4-methylbutane-2-one,-   3-[N-(1,1dimethylbutyl)aminooxy]-4-methylbutane-2-one,-   (N-phenylaminooxy)-4-methylbutane-2-one,-   3-(N-isobutylaminooxy)hexane-2-one,-   3-[N-(1,1dimethylbutyl)aminooxy]hexane-2-one,-   (N-phenylaminooxy)hexane-2-one,-   3-(N-isobutylaminooxy)-4-methylpentane-2-one,-   3-[N-(1,1dimethylbutyl)aminooxy]-4-methylpentane-2-one,-   (N-phenylaminooxy)-4-methylpentane-2-one,-   3-(N-isobutylaminooxy)-pentane-3-one,-   3-[N-(1,1dimethylbutyl)aminooxy]-pentane-3-one,-   (N-phenylaminooxy)-pentane-3-one,-   3-(N-isobutylaminooxy)-2,4-dimethylpentane-3-one,-   3-[N-(1,1dimethylbutyl)aminooxy]-2,4-dimethylpentane-3-one,-   (N-phenylaminooxy)-2,4-dimethylbutane-3-one,-   3-(N-isobutylaminooxy)undecane-2-one,-   3-[N-(1,1dimethylbutyl)aminooxy]undecane-2-one; and-   (N-phenylaminooxy)undecane-2-one.

Examples of the α-aminooxyketones which can be obtained in thisinvention include but are not limited to:

-   3-N-isobutylaminooxy-2-butene-2-one,-   3-N-(1,1-dimethylbutyl)aminooxy-3-butene-2-one,-   3-N-phenylaminooxy-3-butene-2-one,-   3-N-isobutylaminooxy-4-methyl-3-pentene-2-one,-   3-N-(1,1-dimethylbutyl)aminooxy-4-methyl-3-pentene-2-one,-   3-N-phenylaminooxy-4-methyl-3-pentene-2-one,-   1-fluoro-1-(N-isobutylaminooxy)acetone,-   1-fluoro-L-[N-(1,1-dimethylbutyl)aminooxy]acetone,-   1-fluoro-1-(N-phenylaminooxy)acetone,-   1-chloro-1-(N-isobutylaminooxy)acetone,-   1-chloro-1-{N-(1,1dimethylbutyl)aminooxy}acetone,-   1-chloro-1-(N-phenylaminooxy)acetone,-   3-(N-isobutylaminooxy)-2,4-pentanedione,-   3-[N-(1,1-dimethylbutyl)aminooxy]-2,4-pentanedione,-   3-(N-phenylaminooxy)-2,4pentanedione,-   3-(N-isobutylaminooxy)cyclobutanone,-   3-[N-(1,1-dimethylbutyl)aminooxy]cyclobutanone,-   3-(N-phenylaminooxy)cyclobutanone,-   3-(N-isobutylaminooxy)cyclopentanone,-   3-[N-(1,1-dimethylbutyl)aminooxy]cyclopentanone,-   3-(N-phenylaminooxy)cyclopentanone,-   3-(N-isobutylaminooxy)cyclohexanone,-   3-[N-(1,1-dimethylbutyl)aminooxy]cyclohexanone,-   3-(N-phenylaminooxy)cyclohexanone,-   3-(N-isobutylaminooxy)-2-methylcyclohexanone,-   3-[N-(1,1-dimethylbutyl)aminooxy]-2-methylcyclohexanone,-   3-(N-phenylaminooxy)-2-methylcyclohexanone,-   3-(N-isobutylaminooxy)cyclodecanone,-   3-[N-(1,1-dimethylbutyl)aminooxy]cyclodecanone,-   3-(N-phenylaminooxy)cyclodecanone,-   3-(N-isobutylaminooxy)-2-norbornanone,-   3-[N-(1,1-dimethylbutyl)aminooxy]-2-norbornanone,-   3-(N-phenylaminooxy)-2-norbornanone,-   3-(N-isobutylaminooxy)-2-adamantanone,-   3-[N-(1,1-dimethylbutyl)aminooxy]-2-adamantanone,-   3-(N-phenylaminooxy)-2-adamantanone.-   2-(N-isobutylaminooxy)-4-tetrahydropyranone,-   2-[N-(1,1-dimethylbutyl)aminooxy]-4-tetrahydropyranone,-   2-(N-phenylaminooxy)-4-tetrahydropyranone,-   7-(N-isobutylaminooxy)-spiro[4.5]-1,4-dioxy-decane-8-one,-   7-[N-(1,1-dimethylbutyl)aminooxy]spiro[4.5]-1,4-dioxydecane-8-one,-   3-(N-isobutylaminooxy)-1-benzylcarbonylpiperidine-4-one,-   3-[N-(1,1-dimethylbutyl)aminooxy]-1-benzylcarbonylpiperidine-4-one,-   3-(N-phenylaminooxy)-1-benzylcarbonylpiperidine-4-one,-   3-(N-isobutylaminooxy)-4-phenylbutane-2-one,-   3-[N-(1,1-dimethylbutyl)aminooxy-4-phenylbutane-2-one,-   3-(N-phenylaminooxy)-4-phenylbutane-2-one,-   2-(N-isobutylaminooxy)-1-indanone,-   2-[N-(1,1-dimethylbutyl)aminooxy-1-indanone,-   2-(N-phenylaminooxy)-1-indanone,-   1-(N-isobutylaminooxy)-2-indanone,-   1-[N-(1,1-dimethylbutyl)aminooxy-2-indanone,-   1-(N-phenylaminooxy)-2-indanone,-   2-(N-isobutylaminooxy)-1-ketotetrahydronaphthalene,-   2-[N-(1,1-dimethylbutyl)aminooxy-1-ketotetrahydronaphthalene,-   1-(N-phenylaminooxy)-1-ketotetrahydronaphthalene,-   1-(N-isobutylaminooxy)-2-ketotetrahydronaphthalene,-   1-[N-(1,1-dimethylbutyl)aminooxy-2-ketotetrahydronaphthalene,-   1-(N-phenylaminooxy)-2-ketotetrahydronaphthalene,-   1-(N-isobutylaminooxy)-7-methoxy-2-ketotetrahydronaphthalene,-   1-[N-(1,1-dimethylbutyl)aminooxy-7-methoxy-2-ketotetrahydronaphthalene,-   1-(N-phenylaminooxy)-7-methoxy-2-ketotetrahydronaphthalene,-   2′-(N-isobutylaminooxy)-1′-acetophenone,-   2′-[N-(1,1-dimethylbutyl)aminooxy]-1′-acetophenone,-   2′-(N-phenylaminooxy)-1′-acetophenone,-   2′-(N-isobutylaminooxy)-1′-propiophenone,-   2′-[N-(1,1-dimethylbutyl)aminooxy]-1′-propiophenone,-   2′-(N-phenylaminooxy)-1′-propiophenone,-   2-(N-isobutylaminooxy)-1,2-bisphenylethane-1-one,-   2-[N-(1,1-dimethylbutyl)aminooxy]-1,2-bisphenylethane-1-one,-   2-(N-phenylaminooxy)-1,2-bisphenylethane-1-one,-   1-(N-isobutylaminooxy)-1,2-bisphenylbutane-1-one,-   1-[N-(1,1-dimethylbutyl)aminooxy]-1,2-bisphenylbutane-1-one,-   1-(N-phenylaminooxy)-1,2-bisphenylbutane-1-one,-   6-(N-isobutylaminooxy)-3,4-dimethylacetophenone,-   6-[N-(1,1-dimethylbutyl)aminooxy]-3,4-dimethylacetophenone,-   6-(N-phenylaminooxy)-3,4-dimethylacetophenone,-   3′-(N-isobutylaminooxy)-2′-acetonaphthone,-   3′-[N-(1,1-dimethylbutyl)aminooxy]-2′-acetonaphthone,-   3′-(N-phenylaminooxy)-2′-acetonaphthone,-   3′-(N-isobutylaminooxy)-2′-chloroacetonaphthone,-   3′-[N-(1,1-dimethylbutyl)aminooxy]-2′-chloroacetonaphtone; and-   3′-(N-phenylaminooxy)-2′-chloroacetonaphtone.

Example 8 Enantioselective O-Nitroso Aldol/Michael Reactions GeneralProcedures.

All non-aqueous reactions were carried out in oven- or flame-driedglassware under an atmosphere of dry nitrogen unless otherwise noted.Except as otherwise indicated, all reactions were magnetically stirredand monitored by analytical thin-layer chromatography using Whatmanpre-coated silica gel flexible plates (0.25 mm) with F₂₅₄ indicator orMerck pre-coated silica gel plates with F₂₅₄ indicator. Visualizationwas accomplished by UV light (256 nm), with combination of potassiumpermanganate and/or Ninhydrin and/or phosphomolybdic acid, and/or ferricchloride solution as a indicator. Flash column chromatography wasperformed according to the method of Still using silica gel 60 (mesh230-400) supplied by E. Merck. Yields refer to chromatographically andspectrographically pure compounds, unless otherwise noted.

Commercial grade reagents and solvents were used without furtherpurification except as indicated below. Tetrahydrofuran (THF), andEthylene glycol diethyl ether were distilled from sodium-benzophenoneketyl under an atmosphere of dry argon. 2-Cyclohepetene-1-one wasdistilled under P₂O₅. 1,4-Dioxaspiro[4,5]dec-6-en-8-one was preparedaccording to reported method (Kerr, W. J.; McLaughlin, M.; Morrison, A.J.; Pauson, P. L. Org. Lett., 2001, 3, 2945-2948).

Infrared spectra were recorded as thin films on sodium chloride platesusing a Nicolet 20 SXB FTIR. ¹H NMR and ¹³C NMR spectra were recorded ona Bruker Avance 400 (400 MHz ¹H, 100 MHz ¹³C), a Bruker Avance 500 (500MHz ¹H, 125 MHz ¹³C). Chemical shift values (δ) are reported in ppmrelative to Me₄Si (δ 0.0 ppm). The proton spectra are reported asfollows δ (multiplicity, number of protons, coupling constant J).Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q(quartet), p (pentet), h (heptet), m (multiplet) and br (broad).

To the catalyst (0.40 mol) was added enone (2.0 mmol), nitrosobenzene(4.0 mmol) and acetonitrile (4.0 mL). The mixture was allowed to warm to40° C. and was stirred at the same temperature for 15 hours. Thereaction mixture was concentrated under reduced pressure and the residuewas purified by silica gel chromatography to afford the Diels Alderadduct.

Examples

The following Table and examples further demonstrate the scope of thepresent invention. Table 3 demonstrates that the present invention canbe performed with a variety of cyclic α,β-unsaturated ketones andnitroso substrates. Furthermore, the results provided in Table 3 revealthat the heterocyclic product can be obtained in good yields with veryhigh enantioselectivities.

TABLE 3 Reaction Scope^(a)

Exam- yield, ee, entry ple enone R,R ArN═O %^(b) %^(c) 1 2 3 4 8a 8b 8c8d

1a: Me,Me 1b: H,H 1c: Ph, Ph 1d:- (OCH₂CH₂O)— 2a 2a 2a 2a 64 34 56 61 9999 99 98 5 6 7 8  9^(d) 8e 8f 8g 8h 8i

1a 1a 1a 1e: H,H 1e: H,H 2b 2c 2d 2a 2a 47 52 50 14 51 98 98 99 99 99^(a)Reaction was conducted with 20 mol % of catalysit, 1 equiv of enoneand 2 equiv of nitrosobenzene under N₂ atomsphere at 40° C. for 15 h.^(b)Isolated yield. ^(c)ee value was determined by chiral HPLC.^(d)(L)-Proline was used as catalyst.

The methods of purifying the products in Table 3 are discussed below.Also provided are the physical and spectroscopic data of the isolatedproducts along with the chiral columns and experimental conditions usedto separate the enantiomers of the isolated products.

Example 8a 8,8-Dimethyl-3-phenyl-2-oxa-3-aza-bicyclo[2.2.2]octan-6-one

Purification by flash column chromatography with elution by (1:9EtOAc:Hexane) provided as a yellowish oil (64% yield, 99% ee). TLC R_(f)0.7 (EtOAc/Hexane, 1:5); [α]_(D) ²⁹+82.3° (c=1.10, CHCl₃); FTIR (CD₃Cl)ν_(max) 2962, 1743, 1595, 1489, 1028, 992 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)δ 7.31 (t, J=7.4 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 7.00 (t, J=7.3 Hz,2H), □ 4.18-4.19 (m, 1H), 3.51-3.53 (m, 1H), 2.71 (dd, J=18.7 Hz, J=2.7Hz, 1H), 2.48 (dd, J=18.7 Hz, J=3.0 Hz, 1H), 2.31 (dd, J=14.5 Hz, J=3.9Hz, 1H), 1.81 (dd, J=14.5 Hz, J=1.8 Hz, 1H), 1.57 (s, 3H), 1.47 (s, 3H);¹³C NMR (100 MHz, CD₃Cl) δ 208.1, 149.9, 128.9, 122.4, 116.6, 78.2,68.4, 39.8, 34.9, 33.1, 28.6, 27.2; MS (Cl) Exact Mass Calcd forC₁₄H₅N₂O₄(M+H)⁺: 232.1. Found: 232.1. Enantiometric excess wasdetermined by HPLC with Chiralcel AD-H column (97:3 hexane:2-propanol),0.8 mL/min; major enantiomer t_(r)=11.1 min, minor enantiomer t_(r)=10.6min. Enantiomer was obtained as a yellowish oil using D-tetrazolecatalysis using the same method. (61% yield, 99% ee). [α]_(D) ²⁹−79.7°(c=0.56, CHCl₃).

Example 8b 3-Phenyl-2-oxa-3-aza-bicyclo[2.2.2]octan-6-one

Purification by flash column chromatography with elution by (1:4EtOAc:Hexane) provided as a yellowish oil (34% yield, 99% ee); TLC R_(f)0.5 (EtOAc/Hexane 1:3); [α]_(D) ²⁷−216.9° (c=0.6, CHCl₃); FTIR (CD₃Cl)ν_(max) 2965, 1745, 1596, 1488, 1306, 1220, 1174, 986 cm⁻¹; ¹H NMR (500MHz, CD₃Cl) δ 7.31 (t, J=7.4 Hz, 2H), 7.12 (d, J=8.7 Hz, 2H), 7.00 (t,J=7.3 Hz, 1H) 4.19-4.22 (m, 2H), 3.02 (br d, J=18.2 Hz, 1H), 2.47 (dd,J=18.1 Hz, J=3.1 Hz, 1H) 2.26-2.40 (m, 2H), 1.91-1.99 (m, 1H), 1.61-1.68(m, 1H); ¹³C NMR (100 MHz, CD₃Cl) δ 207.1, 150.3, 129.0, 122.2, 116.2,76.9, 56.1, 41.8, 22.4, 21.5; MS (CI) Exact Mass Calcd for C₁₃H₁₅NO₂(M+H)⁺: 204.1, Found: 204.1. Enantiometric excess was determined by HPLCwith Chiralcel AD-H column (90:10 hexane:2-propanol), 11.0 mL/min; majorenantiomer t_(r)=23.4 min, minor enantiomer t_(r)=10.0 min.

Example 8c 3,8,8-Triphenyl-2-oxa-3-aza-bicyclo[2.2.2]octan-6-one

Purification by flash column chromatography with elution by (1:1Hexane:CH₂Cl₂) provided as a yellowish crystal (56% yield, 99% ee); TLCR_(f) 0.7 (CH₂Cl₂); [α]_(D) ³⁰+288.4° (c=0.97, CHCl₃); FTIR (CD₃Cl)ν_(max) 3058, 2361, 2337, 1743, 1596, 1449, 1394, 1032, 998, 909 cm⁻¹;¹H NMR (500 MHz, CD₃Cl) δ 7.31 (t, J=7.4 Hz, 2H), 7.04 (d, J=8.8 Hz,2H), 6.92 (t, J=7.4 Hz, 1H) 4.60 (br d, J=5.8 Hz, 1H), 4.36-4.39 (m,1H), 2.98 (dd, J=18.1 Hz, J=5.5 Hz, 1H), 2.43 (dd, J=18.1 Hz, J=2.1 Hz,1H) 2.07-2.16 (m, 3H), 1.86-1.96 (m, 1H), 1.42-1.56 (m, 1H); ¹³C NMR(100 MHz, CD₃Cl) δ 207.5, 150.0, 129.0, 121.0, 114.7, 83.6, 56.9, 38.8,30.9, 29.7, 18.9; MS (CI) Exact Mass Calcd for C₁₃H₁₅NO₂ (M+H)⁺: 355.2.Found: 355.1. Enantiometric excess was determined by HPLC with ChiralcelAD-H column (95:5 hexane:2-propanol), 1.0 mL/min; major enantiomert_(r)=10.1 min, minor enantiomer t_(r)=8.8 min.

Example 8d8,12-Dioxaspiro-3-phenyl-2-oxa-3-aza-bicyclo[2,2,2]octan-6-one

Purification by flash column chromatography with elution by (1:19EtOAc:CH₂Cl₂) provided as a yellowish oil (61% yield, 98% ee); TLC R_(f)0.6 (EtOAc/CH₂Cl₂, 1:19); [α]_(D) ²⁸−5.4° (c=1.03, CHCl₃); FTIR (CD₃Cl)ν_(max) 2979, 2892, 1747, 1597, 1489, 1227, 1064 cm⁻¹; ¹H NMR (500 MHz,CD₃Cl) δ 7.31 (t, J=7.4 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 7.02 (t, J=7.3Hz, 1H) 4.32 (dd, J=3.6 Hz, J=2.6 Hz, 1H), 4.10-4.15 (m, 1H), 3.97-4.04(m, 3H), 3.92 (t, J=2.9 Hz, 1H), 2.91 (dd, J=15.2 Hz, J=3.9 Hz, 1H),2.88 (dd, J=18.5 Hz, J=2.9 Hz, 1H) 2.66 (dd, J=18.5 Hz, J=2.9 Hz, 1H),2.28 (dd, J=15.2 Hz, J=2.4 Hz, 1H); ¹³C NMR (100 MHz, CD₃Cl) δ 204.9,148.9, 128.8, 122.9, 116.8, 105.5, 77.9, 64.9, 64.8, 64.4, 38.7, 64.5;MS (CI) Exact Mass Calcd for C₁₄H₁₅N₂O₄ (M+H)⁺: 262.1. Found: 262.1.Enantiometric excess was determined by HPLC with Chiralcel AD-H column(90:10 hexane:2-propanol), 1.0 mL/min; major enantiomer t_(r)=20.5 min,minor enantiomer t_(r)=17.3 min.

Example 8e 8,8-Dimethyl-3-p-tolyl-2-oxa-3-aza-bicyclo[2.2.2]octan-6-one

Purification by flash column chromatography with elution by (1:9EtOAc:Hexane) provided as a yellowish crystal (46% yield, 98% ee); TLCR_(f) 0.5 (EtOAc/Hexane 1:5); [α]_(D) ²⁷+44.4° (c=1.32, CHCl₃); FTIR(CD₃Cl) ν_(max) 2961, 1742, 1506, 1028, 994, 817 cm⁻¹; ¹H NMR (400 MHz,CD₃Cl) δ 7.10 (d, J=8.1 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 4.14-4.17 (m,1H), 3.42-3.45 (m, 1H), 2.71 (dd, J=18.7 Hz, J=2.7 Hz, 1H) 2.45 (dd,J=18.7 Hz, J=3.0 Hz, 1H) 2.30 (dd, J=14.4 Hz, J=4.0 Hz, 1H), 2.29 (s,3H), 1.79 (dd, J=14.5 Hz, J=1.8 Hz, 1H) 1.47 (s, 3H), 1.07 (s, 3H); ¹³CNMR (100 MHz, CD₃Cl) δ 208.3, 147.6, 132.0, 129.4, 116.8, 78.2, 68.6,39.9, 34.7, 33.1, 28.6, 27.3, 20.6; C₁₅H₂₀NO₂ (M+H)⁺: 246.2. Found:246.1. Enantiometric excess was determined by HPLC with Chiralcel OD-Hcolumn×2 (99:1 hexane:2-propanol), 0.5 mL/min; major enantiomert_(r)=38.3 min, minor enantiomer t_(r)=40.7 min.

Example 8f3-(3,5-Dimethyl-phenyl)-8,8-dimethyl-2-oxa-3-aza-bicyclo[2.2.2]octan-6-one

Purification by flash column chromatography with elution by (1:9EtOAc:Hexane) provided as a yellowish crystal (52% yield, 98% ee); TLCR_(f) 0.5 (EtOAc/Hexane 1:5); [α]_(D) ²⁷+70.8° (c=0.67, CHCl₃); FTIR(CD₃Cl) ν_(max) 2961, 2921, 2870, 1742, 1595, 1471, 1028, 1006 cm⁻¹; ¹HNMR (400 MHz, CD₃Cl) δ 6.70 (s, 2H), 6.64 (s, 1H), 4.14-4.17 (m, 1H),3.47-3.51 (m, 1H), 2.72 (dd, J=18.7 Hz, J=2.7 Hz, 1H) 2.47 (dd, J=18.7Hz, J=3.0 Hz, 1H) 2.29 (dd, J=14.4 Hz, J=3.9 Hz, 1H), 2.29 (s, 6H), 1.79(dd, J=14.5 Hz, J=2.0 Hz, 1H) 1.46 (s, 3H), 1.07 (s, 3H); ¹³C NMR (100MHz, CD₃Cl) δ 208.4, 150.0, 138.5, 124.2, 114.3, 78.2, 68.2, 39.9, 35.0,33.1, 28.6, 27.3, 21.5; C₁₆H₂₂NO₂ (M+H)⁺: 260.2. Found: 260.2.Enantiometric excess was determined by HPLC with Chiralcel AD-H column(97.5:2.5 hexane:2-propanol), 0.4 mL/min; major enantiomer t_(r)=13.7min, minor enantiomer t_(r)=12.8 min.

Having thus described in detail various embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit and scope of the present invention.

Example 8g3-(4-Bromo-phenyl)-8,8-dimethyl-2-oxa-3-aza-bicyclo[2.2.2]octan-6-one

Solvent system was changed to CH₂Cl₂/MeCN 1:1 (6 mL) was used instead ofuse of CH₂Cl₂. Purification by flash column chromatography with elutionby CH₂Cl₂ provided as a yellowish crystal (50% yield, 99% ee); TLC R_(f)0.6 (CH₂Cl₂); [α]_(D) ²⁷+68.1° (c=2.17, CHCl₃); FTIR (CD₃Cl) ν_(max)2962, 2871, 1742, 1587, 1485, 1436, 1028, 825 cm⁻¹; ¹H NMR (400 MHz,CD₃Cl) δ 7.33 (d, J=8.9 Hz, 2H), 6.90 (d, J=8.9 Hz, 2H), 4.10-4.12 (m,1H), 3.40-3.42 (m, 1H), 2.57 (dd, J=18.7 Hz, J=2.7 Hz, 1H) 2.42 (dd,J=18.7 Hz, J=2.9 Hz, 1H) 2.21 (dd, J=14.6 Hz, J=3.9 Hz, 1H) 1.73 (dd,J=14.5 Hz, J=2.3 Hz, 1H) 1.37 (s, 3H), 1.01 (s, 3H); ¹³C NMR (100 MHz,CD₃Cl) δ 207.4, 149.1, 131.8, 118.2, 114.8, 78.3, 68.3, 39.7, 35.0,33.1, 28.6, 27.2; MS (CI) Exact Mass Calcd for C₁₄H₁₇BrNO₂ (M+H)⁺:310.0. Found: 310.0. Enantiometric excess was determined by HPLC withChiralcel AD-H column (98:2 hexane:2-propanol), 1.0 mL/min; majorenantiomer t_(r)=11.3 min, minor enantiomer t_(r)=15.3 min.

Example 8h 7-Phenyl-6-oxa-7-aza-bicyclo[3.2.2]nonan-9-one

Purification by flash column chromatography with elution by (1:1Hexane:CH₂Cl₂) provided as a yellowish oil (51% yield, 99% ee); TLCR_(f) 0.7 (Hexane/CH₂Cl₂, 1:19); [α]_(D) ²⁹−186.5° (c=1.12, CHCl₃); FTIR(CD₃Cl) ν_(max) 2946, 1736, 1597, 1489, 1204, 1102, 1038, 734 cm⁻¹; ¹HNMR (500 MHz, CD₃Cl) δ 7.31 (t, J=7.4 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H),6.92 (t, J=7.4 Hz, 1H) 4.60 (br d, J=5.8 Hz, 1H), 4.36-4.39 (m, 1H),2.98 (dd, J=18.1 Hz, J=5.5 Hz, 1H), 2.43 (dd, J=18.1 Hz, J=2.1 Hz, 1H)2.07-2.16 (m, 3H), 1.86-1.96 (m, 1H), 1.42-1.56 (m, 1H); ¹³C NMR (100MHz, CD₃Cl) δ 207.5, 150.0, 129.0, 121.0, 114.7, 83.6, 56.9, 38.8, 30.9,29.7, 18.9; MS (CI) Exact Mass Calcd for C₁₃H₁₅NO₂ (M+H)⁺: 218.1. Found:218.1. Enantiometric excess was determined by HPLC with Chiralcel AD-Hcolumn (90:10 hexane:2-propanol), 1.0 mL/min; major enantiomer t_(r)=8.5min, minor enantiomer t_(r)=6.9 min.

1. A process of making an enantioenriched α-aminooxyaldehyde comprisingreacting an aldehyde of formula (I):

with a nitroso compound of formula (IIIa) or (IIIb):

in the presence of a solvent and a catalyst of formula (IVa):

wherein: R represents hydrogen; a substituted or unsubstituted alkylgroup; a substituted or unsubstituted alkoxy group; a substituted orunsubstituted alkoxycarbonyl group; a substituted or unsubstituted arylgroup; or R³ is each independently selected from the group consistingof: hydrogen, halogen, —OR⁵, —OC(O)R⁵, —CN, —C(O)R⁵, —CO₂R⁵,—C(O)NR⁵R^(5′), —NO₂, —NR⁵R^(5′), —NRC(O)R⁵, —NR⁵CO₂R^(5′),—NR⁵S(O)₂R^(5′), —SR⁵, —S(O)R⁵, —S(O)₂R⁵, —S(O)₂NR⁵R^(5′), C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, and 3- to 10-membered heterocyclyl; wherein eachR⁵ and R^(5′) may be independently selected from the group consisting ofhydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl;n is an integer from 0-5; R⁴ is substituted or unsubstituted alkyl; theconfiguration of the stereogenic carbon alpha to the nitrogen on thepyrrolidine ring is the (L) or optionally (D) configuration.
 2. Theprocess of claim 1 wherein: R represents r hydrogen; a substituted orunsubstituted C₁-C₈ alkyl group; a substituted or unsubstituted C₁-C₈alkoxy group; a substituted or unsubstituted C₁-C₈ alkoxycarbonyl group;a substituted or unsubstituted aryl group, wherein the groups whensubstituted are substituted by the group consisting of hydrogen,halogen, —OR⁴, —OC(O)R⁴, —CN, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁴R⁵, —NO₂, —NR⁴R⁵,—NRC(O)R⁴, —NR⁴CO₂R⁵, —NR⁴S(O)₂R⁵, —SR⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NR⁴R⁵,C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl,and 3- to 10-membered heterocyclyl; or R³ is each independently selectedfrom the group consisting of: hydrogen, halogen, —OR⁵, —OC(O)R⁵, —CN,—C(O)R⁵, —CO₂R⁵, —C(O)NR⁵R^(5′), —NO₂, —NR⁵R^(5′), —NRC(O)R⁵,—NR⁵CO₂R^(5′), —NR⁵S(O)₂R^(5′), —SR⁵, —S(O)R⁵, —S(O)₂R⁵,—S(O)₂NR⁵R^(5′), C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to10-membered heterocyclyl; wherein each R⁵ and R^(5′) may beindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, and 3- to O-membered heterocyclyl; R⁴ is asubstituted or unsubstituted C₁-C₈ alkyl, wherein when substituted aresubstituted by the group consisting of halogen, —OR⁵, —OC(O)R⁵, —CN,—C(O)R⁵, —CO₂R⁵, —C(O)NR⁵R^(5′), —NO₂, —NR⁵R^(5′), —NRC(O)R⁵,—NR⁵CO₂R^(5′), —NR⁵S(O)₂R^(5′), —SR⁵, —S(O)R⁵, —S(O)₂R⁵,—S(O)₂NR⁵R^(5′), C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 3- to10-membered heterocyclyl; wherein each R⁵ and R^(5′) may beindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, and 3- to 10-membered heterocyclyl; n is aninteger from 0-3; the configuration of the stereogenic carbon alpha tothe nitrogen on the pyrrolidine ring is the (L) or optionally (D)configuration.
 3. The process of claim 1 wherein the enantioselectivityis greater than 99% enantiomeric excess (ee).
 4. The process of claim 1wherein the catalyst has the following structure.